Hybrid-capture sequencing for determining immune cell clonality

ABSTRACT

In an aspect, there is provided, a method of capturing a population of T-Cell receptor and/or immunoglobulin sequences with variable regions within a patient sample, said method comprising: extracting/preparing DNA fragments from the patient sample; ligating a nucleic acid adapter to the DNA fragments, the nucleic acid adapter suitable for recognition by a pre-selected nucleic acid probe; capturing DNA fragments existing in the patient sample using a collection of nucleic acid hybrid capture probes, wherein each capture probe is designed to hybridize to a known V gene segment and/or a J gene segment within the T cell receptor and/or immunoglobulin genomic loci.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase application under 35 U.S.C. § 371 of International Application No. PCT/CA2017/000084 filed 13 Apr. 2017, which claims priority to U.S. Provisional Application No. 62/322,999 filed 15 Apr. 2016. The entire contents of each of the above-referenced disclosures is specifically incorporated by reference herein without disclaimer.

FIELD OF THE INVENTION

The invention relates to methods of capturing and sequencing immune-associated nucleotide sequences, and more particularly to methods of determining clonality of immune cells.

BACKGROUND OF THE INVENTION

The maturation of lymphocytes is a fascinating process that is marked not only by immunophenotypic changes, but also by discrete and regulated molecular events⁽¹⁻³⁾. As T-cells mature, an important part of the associated molecular “maturation” involves the somatic alteration of the germline configuration of the T-cell receptor (TR) genes to a semi-unique configuration in order to permit the development of a clone of T-cells with an extracellular receptor specific to a given antigen⁽¹⁻³⁾. B-cells undergo a similar maturation process involving different loci that encode the antibody-containing B-cell receptor (BC). These clones, when considered together as a population, produce a repertoire of antigen sensitivity orders of magnitude larger than would be possible by way of inherited immunological diversity alone⁽³⁾ Indeed, the somatic rearrangement of the TR and BR genes is one of the key ontological events permitting the adaptive immune response⁽³⁾.

When molecular carcinogenesis occurs in a lymphoid cell lineage, the result is the selective growth and expansion of the tumoural lymphocytes relative to their normal counterparts⁽²⁾. The so-called precursor (historically termed “lymphoblastic”) lesions are believed to reflect molecular carcinogenesis in lymphoid cells at a relatively immature stage of maturation⁽²⁾. In contrast, if molecular carcinogenesis occurs at a point during or after the process of T-cell receptor gene re-arrangement (TRGR), the result is a “mature” (often also termed “peripheral”) T-cell lymphoma in which the tumour contains a massively expanded population of malignant T-cells with an immunophenotype reminiscent of mature lymphocytes, most if not all bearing an identical TR gene configuration⁽⁴⁾. It is this molecular “homogeneity” of the TR configuration within a T-cell neoplasm that defines the concept of clonality in T-cell neoplasia^((1,2,4)).

The T-cell receptor is a heteroduplex molecule anchored to the external surface of T lymphocytes^((5,21)); there the TR, in cooperation with numerous additional signalling and structural proteins, functions to recognize an antigen with a high degree of specificity. This specificity, and indeed the vast array of potential antigenic epitopes that may be recognized by the population of T-cells on the whole, is afforded by (1) the number of TR encoding regions of a given T-cell receptor's genes as present in the germline; and (2) the intrinsic capacity of the TR gene loci to undergo somatic re-arrangement⁽³⁾. There are four TR gene loci, whose protein products combine selectively to form functional TRs: T-cell receptor alpha (TRA) and T-cell receptor beta (TRB) encode the α and β chains, respectively, whose protein products pair to form a functional α/β TR; T-cell receptor gamma (TRG) and T-cell receptor delta (TRD) encode the γ and δ chains, respectively, whose protein products pair to form a functional γ/δ TR. The vast majority (>95%) of circulating T-cells are of the α/β type^((21,22)); for reasons as yet not fully understood, γ/δ T-cells tend to home mainly to epithelial tissues (e.g. skin and mucosae) and appear to have a different function than the more common α/β type T-cells.

The TRA locus is found on the long arm of chromosome 14 in band 14q11.2 and spans a total of 1000 kilobases (kb)⁽²³⁾; interestingly, sandwiched between the TRA V and J domains, is the TRD locus (14q11.2), itself spanning only 60 kb⁽²⁴⁾. The TRB locus is found on the long arm of chromosome 7 in band 7q35 and spans a total of 620 kb⁽²⁵⁾. The TRG locus is found on the short arm of chromosome 7 in region 7p15-p14 and spans 160 kb⁽⁶⁾.

Within each TR gene locus are a variable number of variable (V) and join (J) segments⁽²³⁻²⁶⁾; additional diversity (D) segments are present within the TRB and TRD loci^((24,25)). These V, D and J segments are grouped into respective V, D and J regions (see FIG. 1-1). In the germline configuration, a full complement of V (numbering from 4-6 in TRG to 45-47 in TRA), D (2 in TRB and 3 in TRD) and J (numbering as few as 4 in TRD to as many as 61 in TRA) segments can be detected, varying based on inheritance⁽²³⁻²⁶⁾. In this configuration, the specificity of any resulting coding sequence would be uniformly based on inherited variation. During maturation, however, somatic mutation (i.e. rearrangement) occurs such that there is semi-random recombination of variable numbers of the V, D and J segments to produce a lineage of cells with a “re-arranged” configuration of TR gene segments. This gene re-arrangement, when later subject to gene transcription and translation, produces a TR unique to the given T-lymphocyte (and its potential daughter cells). This process is represented pictorially in FIG. 1-2. Although the specific details of this re-arrangement process are far beyond the scope of this work, the process is at least partly mediated by enzymes of similar function to those used to perform splicing^((21,22)).

BIOMED-2⁽²⁹⁾ is a product of several years of collaborative expert study, resulting in a thoroughly studied consensus T-cell donality assay. The BIOMED-2 assay includes multiplexed primer sets for both Immunoglobulin (IG) and TR clonality assessment and can be implemented with commercially available electrophoresis systems (e.g. Applied Biosystems fluorescence electrophoresis platforms)⁽²⁹⁾. These commercially available primer sets have the advantage of standardization and ease of implementation. In addition, by virtue of the extensive study performed by the BIOMED consortium, the BIOMED-2 assay has the well-documented advantage of capturing the mono-clonality of the vast majority of control lymphomas bearing productive T-cell receptors (i.e. flow-sorted positive for either α/β or γ/δ T-cell receptors) using the specified TRB and TRG primer sets⁽²⁹⁾. Of note, having been in use for over a decade, the BIOMED-2 has been globally accepted as the diagnostic assay primer set of choice.

The current approach to TRGR testing is subject to a number of technical and practical caveats that dilute the applicability of TRGR testing to the full breadth of real-world contexts.

Because the PCR-based techniques that are employed in TRGR assays are subject to amplicon size restrictions^((29,34)), the sheer size of the TRA locus prevents a complete assay of the TRA gene in clinical settings. Indeed, although of smaller size, the TRB locus as a whole is also prohibitively large to sequence in its germline configuration. It is therefore of no surprise that much of the published data pertaining to the utility and validity of TRGR assays has stemmed from assays specific to only subparts of TRB as well as TRG, a locus of size much more amenable to a single-assay. In addition, since the TRD locus is often deleted after TR gene rearrangement (since it is contained within the TRA locus and excised whenever the TRA locus is rearranged), assays for TRD have also not been as rigorously studied. For this reason, any BIOMED-2-based T-cell clonality assay aimed at directing immunotherapy, requiring a complete sequence-based understanding of the TR genes involved, would be insufficient.

The BIOMED-2 assay is subject to additional technical challenges. As part of the standard TRGR assay, most laboratories rely on the demonstration of electrophoretic migration patterns for the determination of TR clonality. Interpretation of the assay depends on the demonstration (or lack thereof) of a dominant amplicon of specific (albeit not pre-defined) molecular weight, rather than the normal Gaussian distribution of amplicons of variable size. This approach, as has been described previously⁽³⁵⁻³⁷⁾, is subject to interpretative error and other technical problems. Also, given the large amounts of DNA required for the multitude of multiplex tubes making up the assay, the overall assay can very quickly deplete DNA supplies, especially when obtained from limited sample sources.

Finally, and arguably of greatest import, is the issue of diagnostic bias used in the study of TRGR assay performance. More precisely, when laboratories seek to validate a TRGR assay, the requirement of “standard” samples will typically require that the laboratory utilize previously established clonal samples or samples previously diagnosed and accepted to represent clonal entities (e.g. previously diagnosed cases of lymphoma); these samples are in turn compared to “normal” controls. In contrast, the demographics of subsequent “real-life” test samples are unlikely to be so decidedly parsed into “normal” and “abnormal” subsets.

Current T-Cell Receptor (TCR) rearrangement profiling assays rely on targeted PCR amplification of rearranged TCR genomic loci. The simplest method for assessing clonality of T-cells involves qualitative assessment through multiplexed amplification of the individual loci using defined primer sets and interpretation of fragment size distributions according to the BIOMED2 protocol^(A1,2). Next-generation sequencing can be used as a read-out to provide quantitative assessment of the TCR repertoire including detection of low abundance rearrangements from bulk immune cells, or even pairing of the heterodimeric chain sequences with single cell preparation methods^(A3,4). Hybrid-capture based library subsetting is an alternative method to PCR-based amplification that can improve coverage uniformity and library complexity when sample is not limiting and allows for targeted enrichment of genetic loci of interest from individual genes to entire exomes^(A5). In hybrid-capture methods, the formation of probe-library fragment DNA duplexes are used to recover regions of interest^(A6 7,8).

Similar to T-cells, B-cells involved in adaptive immunity also undergo somatic rearrangement of germline DNA to encode a functional B-cell receptor (BR). Like TRs, these sequences comprise by discrete V, D, J segments that are rearranged and potentially altered during B-cell maturation to encode a diversity of unique immunoglobulin proteins. The clonal diversity of B-cell populations may have clinical utility and, similar to T-cell lymphomas, several cancers are characterized by clonal expansion of specific BR/Ig sequences.

SUMMARY OF THE INVENTION

There is described herein, the development of a novel NGS-based T-cell clonality assay, incorporating all four TR loci. The assay was both analytically and clinically validated. For the former, a series of idealized specimens was used, with combined PCR/Electrophoresis and Sanger Sequencing to confirm NGS-data. The latter validation compared NGS results to the current gold standard for clinical T-cell clonality testing (i.e. the BIOMED-2 primer PCR method) on an appropriately-sized minimally-biased sample of hematopathology specimens. In the latter dataset also, the patterns of T-cell clonality were also correlated with clinical, pathologic, and outcome data.

In an aspect, there is provided, a method of capturing a population of T-Cell receptor and/or immunoglobulin sequences with variable regions within a patient sample, said method comprising: extracting/preparing DNA fragments from the patient sample; ligating a nucleic acid adapter to the DNA fragments, the nucleic acid adapter suitable for recognition by a pre-selected nucleic acid probe; capturing DNA fragments existing in the patient sample using a collection of nucleic acid hybrid capture probes, wherein each capture probe is designed to hybridize to a known V gene segment and/or a J gene segment within the T cell receptor and/or immunoglobulin genomic loci.

In an aspect, there is provided, a method of immunologically classifying a population of T-Cell receptor and/or immunoglobulin sequences, the method comprising:

(a) identifying all sequences containing a V gene segment from the sequences of the DNA fragments by aligning the sequences of the DNA fragments to a library of known V gene segment sequences;

(b) trimming the identified sequences in (a) to remove any sequences corresponding to V gene segments to produce a collection of V-trimmed nucleotide sequences;

(c) identifying all sequences containing a J gene segment in the population of V-trimmed nucleotide sequences by aligning the V-trimmed nucleotide sequences to a library of known J gene segment sequences;

(d) trimming the V-trimmed nucleotide sequences identified in (c) to remove any sequences corresponding to J gene segments to produce VJ-trimmed nucleotide sequences;

(e) identifying any D gene segment comprised in the VJ-trimmed nucleotide sequences identified in (d) by aligning the VJ-trimmed nucleotide sequences to a library of known D gene segment sequences;

(f) for each VJ-trimmed nucleotides sequence identified in (d), assembling a nucleotide sequence comprising the V gene segment, any D gene segment, and the J gene segment identified in steps (a), (e) and (c) respectively;

(g) selecting from the nucleotide sequence assembled in step (f) a junction nucleotide sequence comprising at least the junction between the V gene segment and the J gene segment, including any D gene segment, the junction nucleotide sequence comprising between 18 bp and 140 bp, preferably 40-100 bp, further preferably about 80 bp;

and optionally (h) and (i):

(h) translating each reading frame of the junction nucleotide sequence and its complementary strand to produce 6 translated sequences; and

(i) comparing the 6 translated sequences to a library of known CDR3 regions of T-Cell receptor and/or immunoglobulin sequences to identify the CDR3 region in the DNA fragments.

In an aspect, there is provided, a method of identifying CDR3 regions in T-Cell receptor and/or immunoglobulin sequences, the method comprising:

(a) identifying a V gene segment comprised in the immunoglobulin sequence by aligning the immunoglobulin sequence to a library of known V gene segment sequences;

(b) identifying a J gene segment comprised in the immunoglobulin sequence by aligning the immunoglobulin sequence to a library of known J gene segment sequences;

(c) if V and J gene segments are identified, then comparing the immunoglobulin sequence to a library of known CDR3 regions of T-Cell receptor and/or immunoglobulin sequences to identify any CDR3 region in the immunoglobulin sequence.

BRIEF DESCRIPTION OF FIGURES

These and other features of the preferred embodiments of the invention will become more apparent in the following detailed description in which reference is made to the appended drawings wherein:

FIG. 1: TRGR Assay Wet-Bench Work-Flow Schematic. 1, DNA isolation; 2, Shearing (˜200 bp); 3, Library Production; 4, Hybridization with Biotinylated DNA Probes; 5, Enrichment with Streptavidin-Bound Paramagnetic Beads; 6, PCR; 7, Illumina sequencing.

FIG. 2: Schematic Representation of V and J Gene Probe Placement Relative to the Germline. The germline V-genes are highlighted in solid red, with 100 bp probe placement shown above; probes are oriented inward and abut the 5′ & 3′ ends of the germline V-gene configuration. The germline J-genes are highlighted in solid blue, with 100 bp probe placement shown above; J-gene probes cover the entire J-gene, and on occasion some flanking extragenic sequence.

FIG. 3-1: Read Length Simulation Results. In this simulation, the percent of total BWA-detectable VDJ gene combinations obtained by reference sequence concatenation was computed. Note that a plateau of maximal sensitivity could be inferred with a read length of approximately 200 bp or more.

FIG. 3-2: Empirical determination of MATLAB alignment score cut-off values.

FIG. 3-3: First Run TapeStation tracings Pre-Library (post-shearing) vs. Post-Library Preparation. In this tableau, each specimen's electropherogram tracing before & after library preparation is displayed (one above the other) in order to compare the library preparation adapter/barcode ligation success & expected increase in average fragment length of approximately 100 bp. Part 1: Specimens A037, L2D8, OV7 & CEM. Part 2: Specimens EZM, Jurkat, TIL2, MOLT4, STIM1, SUPT1.

FIG. 3-4: PEAR Algorithm Read-Merge & Assembly Results for each first-run specimen.

FIG. 3-5: First Run Comparison of PEAR-produced input Reads (blue) vs. Reads-on-Target (yellow).

FIG. 3-6: First Run Summary Coverage Statistics. Mean Depth of Coverage and Percent of Genes with Greater than 100× Coverage shown.

FIG. 3-7A: First Run Lymphocyte Sample Circos Plots. The ideogram represents all intra-locus V-J combinations (color coded by locus: TRA red; TRB blue; TRD yellow; TRG green); the height and width of the gray bars are determined by read counts of identical V & J gene name and CDR3 sequence triads.

FIG. 3-7B: First Run Cell Line Circos Plots. The ideogram represents all intra-locus V-J combinations (color coded by locus: TRA red; TRB blue; TRD yellow; TRG green); the height and width of the gray bars are determined by read counts of identical V & J gene name and CDR3 sequence triads.

FIG. 3-7C: Tableaus of coverage histograms for V and J genes across all four TR loci for each of the six lymphocyte samples. Specimens more characteristically “polyclonal” show a uniform coverage across most if not all genes, at greater than 100×; specimens more seemingly “clonal” tend to show at least a subset of genes at coverage less than 100×.

FIG. 3-7D: Tableau of coverage histograms for V and J genes across all four TR loci for each of the four cell line samples. These clonal specimens uniformly show at least a subset of genes at coverage less than 100×.

FIG. 3-8: First Run TRSeq algorithm performance metrics relative to the IMGT/High V-Quest Pipeline. This boxplot highlights the percent concordance of calls made by the TRSeq pipeline across all four loci and over all 10 specimens for each of overall read rearrangement status, and named V, D, and J-gene concordance relative to the calls made by the IMGT/High V-Quest system.

FIG. 3-9: Analytical Validation Electrophoresis Composite Gel Photographs. Gels are listed by Specimen Name. Primer Combinations (V-gene forward & J-gene reverse complement) are listed along the x-axes; 100 bp ladders are shown along the y-axes. Interpretation of the banding patterns, by expected amplicon size and by intensity, is outlined in Table 3.1A.

FIG. 3-10A: ROC Plot by Strong PCR/Electrophoresis Band. ROC Curve Cut-offs vary by normalized read count shown.

FIG. 3-10B: ROC Plot, Any PCR/Electrophoresis Band of Reasonable Molecular Weight. ROC Curve Cut-offs vary by normalized read count shown.

FIG. 3-11: Analytical Validation Sanger Sequencing Results. In this analysis, the CDR3 sequence from each TRGR configuration is aligned to the corrected Sanger Sequence (with the number of reads of each configuration also tallied); the diagrams below delineate this alignment process for each of the PCR reactions submitted for Sanger Sequencing, as highlighted in FIG. 3-10, excluding those cases rejected due to false-positive amplification using the TRGJ2 primer and cases not containing TRSeq-identifiable CDR3 sequences (for a total of 32 of 47 reactions).

FIG. 3-12: Sanger Sequencing Receiver-Operating Characteristic Curve. Using a k-mer-based analysis, the TRSeq-generated CDR3 sequences were compared to the Sanger Sequence results. For each applicable primer configuration, the corresponding TRSeq-generated CDR3 sequence was aligned using PHRED-based quality-score adjustment as a k-mer across the length of the Sanger (“reference”) Sequence. If the optimal alignment from this process was present within the sequence window in which a CDR3 was predicted to exist, the CDR3 read configuration was classified as “compatible.” This “compatibility” scoring system was then compared to the read counts of the appertaining TRSeq configuration to generate a ROC curve.

FIG. 3-13A: Dilution Experiment Curve by V-J Configurations. In this experiment, mean raw read counts (+/−standard deviation) of the various Jurkat-specific V-J combinations are tallied for each of the dilutions.

FIG. 3-13B: Dilution Experiment Curve by V-J Configurations, Excluding Dilution 1. In this plot, the data from FIG. 3-16A are re-analyzed after excluding dilution 1, in order to highlight an apparently linear correlation between raw read counts and expected number of Jurkat cells at the lower end of the dilution series.

FIG. 3-14: Dilution Experiment Curve by Clonotype. In this experiment, mean raw read counts (+/−standard deviation) of the various Jurkat-specific clonotypes (i.e. V & J-gene & specific CDR3 sequence), allowing for acceptable CDR3 sequence error per the methods of Bolotin, et al. (27), are tallied for each of the dilutions.

FIG. 3-15: NTRA—BIOMED-2 Comparison. ROC analysis for classification by maximum TRB and TRG dominant clonotype read count-to-background ratio relative to overall BIOMED-2 results (taken as positive or negative for a clonal population).

FIG. 3-16: Coverage ROC Curve: Classification by BIOMED-2 Clonality Assessment. Cut-offs vary by coverage, as set-out in the legend.

FIG. 4: T cell receptor hybrid capture reflects expected clonal make-up of bulk blood cells, tumour infiltrating lymphocytes, T-cell cancer cell line.

FIG. 5: A custom Bash/Python/R pipeline is employed for analysis of paired read sequencing data generated by Illumina DNA sequencing instruments from the hybrid-capture products. This pipeline consists of four major steps: (1) Merging of the paired reads; (2) Identification of specific V, J, and D genes within the fragment sequence; (3) identification of the V/J junction position as well as the antigen specificity determining Complementarity Determining Region 3 (CDR3) sequence at this site; (4) Calculation and visualization of capture efficiency and clone frequency within and across individual samples.

FIG. 6: An overview of the CapTCR-Seq hybrid-capture method. (A) Hybrid-capture method experimental flow diagram. Fragments are colored based on whether they contain V-region targets (blue), J-region targets (red), D-regions (green), constant regions (yellow) or non-TCR coding regions (black). (B) V(D)J rearrangement and CDR3 sequence detection algorithm flow diagram. (C) Number of unique VJ pairs recovered relative to library DNA input amount for one-step V capture of A037 PBMC derived libraries. (D) A037 polyclonal human beta locus VJ rearrangements determined by CapTCR-seq. (E) A037 polyclonal human beta locus VJ rearrangements determined by a PCR-based profiling service. (F) Subtractive comparison between CapTCR-seq and PCR-based profiling service. Red indicates relative enrichment of indicated pair by CapTCR-seq while blue indicates relative enrichment of indicated pair by PCR-based profiling.

FIG. 7: Cell line and tumor isolate T-cell clonality. Boxes represent individual unique VJ pairs and box size reflects abundance in sample. Samples ordered by decreasing donality. (A) Beta chain VJ rearrangements. (B) Gamma chain VJ rearrangements. (C) L2D8 Gp100 antigen specific beta locus VJ rearrangements determined by CapTCR-seq. (D) L2D8 Gp100 antigen specific beta locus VJ rearrangements determined by a PCR-based profiling service. (E) Subtractive comparison between CapTCR-seq and PCR-based profiling service. Red indicates relative enrichment of indicated pair by CapTCR-seq while blue indicates relative enrichment of indicated pair by PCR-based profiling.

FIG. 8: Clinical sample T-cell clonality. Boxes represent individual clones with unique VJ rearrangements and box size reflects abundance in sample. Clonality assessments are indicated as either green (clonal), red (polyclonal), or yellow (not performed). Samples are ordered left to right in terms of increasing CapTCR-Seq clonality with an asterisk indicating disagreement between CapTCR-Seq and BIOMED2 assessments. (A) Beta chain VJ rearrangements. (B) Gamma chain VJ rearrangements.

FIG. 9: (A) A037 healthy reference sample: Unique alpha chain VJ combinatorial counts. (B) A037 healthy reference sample: Unique beta chain VJ combinatorial counts. (C) A037 healthy reference sample: Unique gamma chain VJ combinatorial counts. (D) A037 healthy reference sample: Unique delta chain VJ combinatorial counts. (E) Comparison of unique VJ fraction prevalence between A037 samples assessed by ImmunoSEQ and CapTCR-seq. Each point represents fraction of total observed rearrangements for each V or J allele.

FIG. 10: Comparison of different method variants in terms of yielded average unique CDR3 sequences (normalized to reads and library input).

FIG. 11: Comparison of different hybridization and capture temperatures in terms of yielded average unique CDR3 sequences (normalized to reads and library input).

FIG. 12: Comparison of different depletion clean-up steps in terms of yielded average unique CDR3 sequences (normalized to reads and library input).

FIG. 13: Comparison of different permutations of iterative captures in terms of yielded average unique CDR3 sequences (normalized to reads and library input).

FIG. 14: CD3+ T cell fraction dilution curve. Comparison of average unique CDR3 sequences (normalized to reads and library input) for samples with varying amounts of source material added to generate the library (10 ng-250 ng).

FIG. 15: PBMC fraction dilution curve. Comparison of average unique CDR3 sequences (normalized to reads and library input) for samples with varying amounts of source material added to generate the library (10 ng-250 ng).

FIG. 16: PBMC fraction cDNA dilution curve. Comparison of average unique CDR3 sequences (normalized to reads and library input) for samples with varying amounts of source material added to generate the library (5 ng-40 ng).

FIG. 17: A037 VJ repertoire saturation curve. All samples derived from a single patient blood draw. Samples are drawn on the X-axis and black dots represents the fraction of new VJ combinations not seen before in previous samples from left to right and graphed on the right axis. Blue curve represents total combined number of unique VJ combinations across all samples from left to right and graphed on the left axis (log). Red curve represents per sample number of unique VJ combinations graphed on the left axis (log).

FIG. 18: A037 CDR3 repertoire saturation curve. All samples derived from a single patient blood draw. Samples are drawn on the X-axis and black dots represents the fraction of new CDR3 combinations not seen before in previous samples from left to right and graphed on the right axis. Blue curve represents total combined number of unique CDR3 combinations across all samples from left to right and graphed on the left axis (log). Red curve represents per sample number of unique CDR3 combinations graphed on the left axis (log).

FIG. 19: Comparison of VJ beta locus repertoire for A037 sample derived from genomic DNA (panel 1) and from cDNA (panel 2). A subtractive heatmap is shown in panel 3 that shows differences in overall repertoire between the two samples. Red indicates deviation for genomic, while blue indicates deviation for cDNA.

FIG. 20: Prevalence comparison of the top 1000 beta locus CDR3 in the genomic DNA set compared with their prevalences in the cDNA set.

FIG. 21: Beta locus VJ repertoire of an adoptive cell transfer immunotherapy patient over time. Samples are indicated on the X axis ordered by date of sample. VJ clones are ordered in all samples according to prevalence in the TIL infusion product and the top nine most prevalent TIL infusion clones are colored.

FIG. 22: Nine most prevalent TIL infusion clones at the Beta locus of an adoptive cell transfer immunotherapy patient over time. Samples are indicated on the X axis ordered by date of sample.

FIG. 23: TCR signal from an unselected cDNA library (red) and the same library following capture CapTCR-Seq (blue). Samples are indicated on the Y axis, while unique CDR3 counts is graphed on the X axis (log).

FIG. 24: TCR total signal (VJ counts) and repertoire diversity (unique CDR3 counts) for all samples from five patients.

FIG. 25: TCR total signal (VJ counts) and repertoire diversity (unique CDR3 counts) for all tumor samples from five patients.

FIG. 26: Patient A: Stacked barplots of unique VJ rearrangements for alpha locus tumor (panel 1), beta locus tumor (panel 2), alpha locus baseline blood (panel 3), and beta locus baseline blood (panel 4). Each box represents a VJ rearrangement and box size corresponds to prevalence within sample (Y axis).

FIG. 27: Top ten most prevalent beta locus rearrangements from patient A tumor.

FIG. 28: Sample fractions within all patient A samples for top ten most prevalent VJ rearrangements in tumor. Alpha locus (panel 1), beta locus (panel 2), gamma locus (panel 3), delta locus (panel 4).

DETAILED DESCRIPTION

In the following description, numerous specific details are set forth to provide a thorough understanding of the invention. However, it is understood that the invention may be practiced without these specific details.

The advantages of high-throughput DNA sequencing technologies could potentially be applied to T-cell clonality testing. The nature of T-cell gene diversity, requiring the consideration of potential variability arising from four distinct gene loci, makes obvious the benefit of multiplexing; what has traditionally required multiple separate tests could be combined in a single reaction. The capacity of modern DNA sequencing technologies to query longer contiguous segments of DNA in greater quantities relative to traditional techniques also provides an opportunity to explore the potential meaning of TRA and TRB sequence rearrangements. Sequence-level data might afford a greater ease of assay result interpretation. Indeed, the generation of sequence-level data in a TRGR assay would likely be much more informative than gross estimates of DNA electrophoretic migration patterns when disease trends are being studied; the high-level analysis of such data might help the identification of heretofore hidden patterns of TR rearrangement in specific T-cell lymphoma subtypes. The issue of replicate numbers for establishing test sensitivity/specificity can be easily overcome by exploiting the high-throughput capacity of modern DNA sequencing platforms; for a comparable investment of time (and possibly cost), sequencing-based approach to TRGR could perform a greater number of individual tests, thereby potentially allowing a more statistically robust estimate of test performance.

Traditional sequencing uses PCR-based techniques to markedly amplify input template DNA, thus improving the sensitivity of detection during the sequencing step. Indeed, many sequencing-based technologies still perform directed library preparation using PCR-based techniques to isolate and sequence regions of interest⁽³⁸⁾. By this approach, one might employ specific primer sets to enrich for regions of interest in the library preparation step. In the context of TRGR, however, a primer-based approach to library preparation would be challenging: in order to provide the sufficient breath of coverage required to interrogate the status of the vast number of TR genes (especially in the TRA locus), a massive array of primers would be required. Although it is theoretically possible to prime multiple regions in tandem, previous data suggest that such an approach might open the door to the possibility of technical error (for a more thorough review of the details of these errors and the studies that have supported this evidence, see⁽³⁸⁾). In the context of TRGR, furthermore, a primer-based approach to library preparation introduces the possibility of allele dropout when the assay attempts to prime a rearranged gene based on the known germline configuration (an easily digestible review to this effect may be found here⁽³⁹⁾).

A paradigm shift away from PCR primer-directed amplification of genomic areas of interest was required for sequencing experiments aimed at large numbers of genes. Indeed most sequencing-based technologies rather employ the upfront production of vast libraries of template oligonucleotides followed by a series of template enrichment steps⁽³⁾. These latter steps may simply involve the extraction of DNA of specific lengths or quality, or rather the focus may be to enrich DNA containing specific sequences of interest. In the latter scenario, when specific sequence motifs are enriched for during library preparation, the resulting sequencing data will be enriched for the sequences of interest. Additionally, using the above stepwise approach, library preparation may be generalized to permit the enrichment of specific sequences out of a mix of “all” sequences produced from the primary non-specific amplification step; it is easy to see how this approach may be used to permit multiple separate assays using different enrichment approaches applied to a single input library⁽⁴⁰⁾.

Hybrid capture is a form of library enrichment in which a library is probed for known sequences of interest using tagged nucleic acid probes followed by a subsequent “pull-down” of the tagged hybrids⁽³⁸⁾; for example, DNA probes tagged with biotin can be efficiently enriched when hybridization is followed by a streptavidin enrichment step^((28,40-43)). The biotin/streptavidin enrichment procedure is schematized in FIG. 2-1A. In reference to the assessment of TRGR, this approach has the advantage of enriching TR genes based on the available well-defined germline TR gene sequences, which can be performed in a massively parallel fashion using several hundred probes. Notably, this approach also allows for enrichment of rearranged sequences as the hybrid-capture probes can also hybridize to (and therefore enrich for) subsequences of the rearrangement product. This latter “pull-down” of rearranged TR genes would be difficult using a primer-only approach to library preparation.

Rather than restricting the assessment of test performance of the above DNA sequencing approaches to a pre-set (and potentially biased) sample of “malignant” and “benign” T-cell lymphoproliferative disorders, a more prudent sampling rubric might use a “real-world” series of consecutive samples taken from a population as similar to the “test population” as possible. In the context of TRGR validation, such a sample might consist of a series of consecutive tissue samples from patients being worked-up by a hematologist and submitted for molecular (i.e. T-cell clonality) assessment. The overall sample size could be established based on an estimate of the historical incidence of T-cell lymphomas in such a population, such that the total size of the sample is adequately large to include a sufficient “expected” number of clonal T-cell lymphoproliferative disorders.

In many validation studies, the final pathology diagnosis is used as the gold standard against which the novel test is measured⁽⁴⁴⁾. While not unreasonable, there are arguments against employing such an approach. Of foremost concern is the potential for diagnostic or interpretative error, by which “true positivity” of disease could be misappropriated⁽⁴⁴⁾. In the realm of T-cell lymphomas, given at least partly due to their rarity, the frequent lack of pathologist experience might make this problem more likely. Furthermore, evidence indicates that even when diagnoses are based on consensus or panel based interpretation, the possibility of diagnostic bias by dominant opinion should be considered⁽⁴⁵⁾.

When a single clearly-defined outcome measure does not exist (or is limited by bias), a composite gold-standard might be more appropriate⁽⁴⁶⁾. Composite gold-standards might include a number of individual test results or clinical observations logically combined to produce “positive” or “negative” composites⁽⁴⁶⁾; of key import is that (1) well-defined rules of composition be set out a priori and (2) the number of samples or subjects with each of the composite test results should be well-described (u). Ideally, all samples or subjects should be evaluated using each of the composite tests (4).

In order to best study a novel test of TLPDs, rather than limiting the reference test to the gold-standard BIOMED-2 T-cell clonality assay or to pathology diagnoses, a series of both individual and composite references might be considered. From the perspective of analytical validity, one might consider validating an sequencing-based TRGR assay using standard PCR techniques followed by Sanger sequence verification. Since the sequences of each of the TR V and J genes are known, forward and reverse primer sets for each V and J genes, respectively, identified by the capture and sequencing assay could be used to verify that the detected result is valid; this could be followed by Sanger sequencing to validate the result of the DNA sequencing result (with deference specifically to the CDR3 variability-defining region).

In another experiment, one might consider comparing a sequencing-based TRGR result to the BIOMED-2 result (with each test applied to all specimens under study). The primary limitation of this approach would be that the BIOMED-2 assay, as explained above, does not test for any TRA rearrangements; thus this comparison alone would be insufficient. Additional comparisons might involve assessment of the sensitivity and specificity of each of the BIOMED-2 and sequencing-based TRGR assays at identifying benign or malignant TLPDs. For this, a composite gold-standard including histologic features (i.e. pathology diagnosis), immunophenotypic features, additional molecular features (as available, e.g. cytogenetic changes), clinical observations (e.g. presence or absence of features of malignancy), and outcome results (e.g. significant deviation in individual patient survival from the median) might be considered. The clinical validity of the sequencing results could thus be assessed against the current diagnostic standard by means of a much more thorough evaluation.

T-cell lymphomas are cancers of immune cell development that result in clonal expansion of malignant clones that dominate the T-cell repertoire of affected patients. Therefore, clonality assessment of these cell populations is essential for the identification and monitoring of T-cell lymphomas. We have developed a hybrid-capture method that recovers rearranged sequences of T-cell receptor (TCR) chains from all four classes (alpha, beta, gamma, and delta loci) in a single reaction from an Illumina sequencing library. We use this method to describe the TCR V(D)J repertoire of monoclonal cancer cell lines, tumor-derived lymphocyte cultures, and peripheral blood mononuclear cells from a healthy donor, as well as a set of 63 clinical isolates sent for clinical clonality testing for suspected T-cell lymphoma. PCR amplification and Sanger sequencing confirmed cell line and tumor predominant rearrangements, individual beta locus V and J allele prevalence was well correlated with results from a commercial PCR-based DNA sequencing assay with an r² value of 0.94, and BIOMED2 PCR fragment size beta and gamma locus clonotyping of clinical isolates showed 73% and 77% agreement respectively. Our method allows for rapid, high-throughput and low cost characterization of TCR repertoires that will enhance sensitivity of tumor surveillance as well as facilitate serial analysis of patient samples with a quantitative read-out during clinical immunotherapy interventions.

In an aspect, there is provided, a method of capturing a population of T-Cell receptor and/or immunoglobulin sequences with variable regions within a patient sample, said method comprising: extracting/preparing DNA fragments from the patient sample; ligating a nucleic acid adapter to the DNA fragments, the nucleic acid adapter suitable for recognition by a pre-selected nucleic acid probe; capturing DNA fragments existing in the patient sample using a collection of nucleic acid hybrid capture probes, wherein each capture probe is designed to hybridize to a known V gene segment and/or a J gene segment within the T cell receptor and/or immunoglobulin genomic loci.

As used herein, “T-Cell Receptor” or “TCR” means a molecule found on the surface of T lymphocytes (or T cells), preferably human, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The TCR is a disulfide-linked membrane-anchored heterodimeric protein normally consisting of the highly variable alpha (a) and beta (P) chains expressed as part of a complex with the invariant CD3 chain molecules. T cells expressing this receptor are referred to as α:β (or αβ) T cells, though a minority of T cells express an alternate receptor, formed by variable gamma (γ) and delta (δ) chains, referred as γδ T cells. Each chain is composed of two extracellular domains: Variable (V) region and a Constant (C) region. The variable domain of both the TCR α-chain and β-chain each have three hypervariable or complementarity determining regions (CDRs). CDR3 is the main CDR responsible for recognizing processed antigen.

The terms “antibody” and “immunoglobulin”, as used herein, refer broadly to any immunological binding agent or molecule that comprises a human antigen binding domain, including polyclonal and monoclonal antibodies. Depending on the type of constant domain in the heavy chains, whole antibodies are assigned to one of five major classes: IgA, IgD, IgE, IgG, and IgM. Several of these are further divided into subclasses or isotypes, such as IgG1, IgG2, IgG3, IgG4, and the like. The heavy-chain constant domains that correspond to the difference classes of immunoglobulins are termed α, δ, ε, γ and μ, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known. The “light chains” of mammalian antibodies are assigned to one of two clearly distinct types: kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains and some amino acids in the framework regions of their variable domains. The variable domains comprise the complementarity determining regions (CDRs). The methods described herein may be applied to immunoglobulin sequences, including B-cell immunoglobulin sequences.

“V gene segments”, “J gene segments” and “D gene segments” as used herein, refer to the variable (V), joining (J), and diversity (D) gene segments involved in V(D)J recombination, less commonly known as somatic recombination. V(D)J recombination is the mechanism of genetic recombination that occurs in developing lymphocytes during the early stages of T and B cell maturation. The process results in the highly diverse immune repertoire of antibodies/immunoglobulins (Igs) and T cell receptors (TCRs) found on B cells and T cells, respectively.

The term “nucleic acid” includes DNA and RNA and can be either double stranded or single stranded.

The term “probe” as used herein refers to a nucleic acid sequence that will hybridize to a nucleic acid target sequence. In one example, the probe hybridizes to the RNA biomarker or a nucleic acid sequence complementary thereof. The length of probe depends on the hybridization conditions and the sequences of the probe and nucleic acid target sequence. In one embodiment, the probe is at least 8, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 400, 500 or more nucleotides in length.

The term “adapter” as used herein refers a moiety capable of conjugation to a nucleic acid sequence for a particular purpose. For example, the adapter may be used to identify or barcode the nucleic acid. Alternatively, the adapter may be a primer which can be used to amplify the nucleic acid sequence.

The term “hybridize” or “hybridizable” refers to the sequence specific non-covalent binding interaction with a complementary nucleic acid. In a preferred embodiment, the hybridization is under stringent conditions. Appropriate stringency conditions which promote hybridization are known to those skilled in the art, or can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1 6.3.6. For example, 6.0×sodium chloride/sodium citrate (SSC) at about 45° C., followed by a wash of 2.0×SSC at 50° C. may be employed.

In some embodiments, the method further comprises sequencing the captured DNA fragments, wherein the sequencing can be used to determine clonotypes within the patient sample. Various sequencing techniques are known to the person skilled in the art, such as polymerase chain reaction (PCR) followed by Sanger sequencing. Also available are next-generation sequencing (NGS) techniques, also known as high-throughput sequencing, which includes various sequencing technologies including: Illumina (Solexa) sequencing, Roche 454 sequencing, Ion torrent: Proton/PGM sequencing, SOLiD sequencing. NGS allow for the sequencing of DNA and RNA much more quickly and cheaply than the previously used Sanger sequencing. In some embodiments, said sequencing is optimized for short read sequencing.

In some embodiments, the method further comprises amplifying the population of sequences using nucleic acid amplification probes/oligonucleotides that recognize the adapter prior to said sequencing.

In some embodiments, the method further comprises fragmenting DNA extracted from the patient sample to generate the DNA fragments.

In some embodiments, the ligating step is performed before the capturing step.

In some embodiments, the capturing step is performed before the ligating step.

The term “patient” as used herein refers to any member of the animal kingdom, preferably a human being and most preferably a human being that has AML or that is suspected of having AML.

The term “sample” as used herein refers to any fluid, cell or tissue sample from a subject which can be assayed for nucleic acid sequences. In some embodiments, the patient sample comprises tissue, urine, cerebral spinal fluid, saliva, feces, ascities, pleural effusion, blood or blood plasma.

In some embodiments, the patient sample comprises cell-free nucleic acids in blood plasma.

In some embodiments, the clonality analyses described herein may be use to track clonality across samples types.

In some embodiments, the hybrid capture probes are at least 30 bp in length. In a further embodiment, the hybrid capture probes are between 60 bp and 150 bp in length. In a further embodiment, the hybrid capture probes are between 80 bp and 120 bp in length. In a further embodiment, the hybrid capture probes are about 100 bp in length.

In some embodiments, the hybrid capture probes hybridize to at least 30 bp, preferably 50 bp, more preferably 100 bp of the V gene segment and/or J gene segment.

In some embodiments, the hybrid capture probes hybridize to at least a portion of the V gene segment and/or J gene segment at either the 3′ end or the 5′ end of the V gene segment and/or J gene segment respectively.

In some embodiments, the screening probes hybridize to at least a portion of the V gene segment.

In some embodiments, the screening probes hybridize to at least a portion of the V gene segment at the 3′ end.

In some embodiments, hybridizing comprises hybridizing under stringent conditions, preferably very stringent conditions.

In some embodiments, the collection of nucleic acid hybrid capture probes comprise at least 2, 5, 10, 20, 30, 80, 100, 300, 400, 500, 600, 700, 800 or 900 unique hybrid capture probes.

In some embodiments, the collection of nucleic acid hybrid capture probes is sufficient to capture at least 50%, 60%, 70%, 80%, 90% or 99% of known T-Cell receptor and/or immunoglobulin loci clonotypes.

In some embodiments, the hybrid capture probes are immobilized on an array.

In some embodiments, the hybrid capture probes comprise a label. In a further embodiment, the label is used to distinguish between sequences bound to the screening probes and unbound double stranded fragments, and preferably the capture is performed in solution.

In some embodiments, preparing the DNA fragments comprises extracting RNA from the patient sample and preparing corresponding cDNA.

In some embodiments, the method further comprises a depletion step, comprising depleting the DNA fragments of non-rearranged sequences using probes that recognize nucleic acid sequences adjacent to V and/or J gene segments in the genome. In some embodiments, the capturing of DNA fragments using V gene segment and J gene segment hybrid capture probes is performed in separate steps, and in any order with the depletion step, preferably in the following order: J gene capture, depletion, then V gene capture.

In an aspect, there is provided, a method of immunologically classifying a population of T-Cell receptor and/or immunoglobulin sequences, the method comprising:

-   -   (a) identifying all sequences containing a V gene segment from         the sequences of the DNA fragments by aligning the sequences of         the DNA fragments to a library of known V gene segment         sequences;     -   (b) trimming the identified sequences in (a) to remove any         sequences corresponding to V gene segments to produce a         collection of V-trimmed nucleotide sequences;     -   (c) identifying all sequences containing a J gene segment in the         population of V-trimmed nucleotide sequences by aligning the         V-trimmed nucleotide sequences to a library of known J gene         segment sequences;     -   (d) trimming the V-trimmed nucleotide sequences identified         in (c) to remove any sequences corresponding to J gene segments         to produce VJ-trimmed nucleotide sequences;     -   (e) identifying any D gene segment comprised in the VJ-trimmed         nucleotide sequences identified in (d) by aligning the         VJ-trimmed nucleotide sequences to a library of known D gene         segment sequences;     -   (f) for each VJ-trimmed nucleotides sequence identified in (d),         assembling a nucleotide sequence comprising the V gene segment,         any D gene segment, and the J gene segment identified in steps         (a), (e) and (c) respectively;     -   (g) selecting from the nucleotide sequence assembled in step (f)         a junction nucleotide sequence comprising at least the junction         between the V gene segment and the J gene segment, including any         D gene segment, the junction nucleotide sequence comprising         between 18 bp and 140 bp, preferably 40-100 bp, further         preferably about 80 bp;     -   and optionally (h) and (i):     -   (h) translating each reading frame of the junction nucleotide         sequence and its complementary strand to produce 6 translated         sequences; and     -   (i) comparing the 6 translated sequences to a library of known         CDR3 regions of T-Cell receptor and/or immunoglobulin sequences         to identify the CDR3 region in the DNA fragments.

Alternatively, step (h) may be searching the 6 translated sequences for flanking invariable anchor sequences to define the intervening T-Cell receptor and/or B-cell receptor CDR3 sequences encoded by the DNA fragments.

In some embodiments, the method further comprises, prior to step (a), aligning left and right reads of overlapping initial DNA fragments to produce the DNA fragments on which step (a) is performed.

In some embodiments, steps (a), (c), (e) are performed with BLASTn and step (i) is performed using expression pattern matching to known sequences and IMGT annotated data.

In an aspect, there is provided, a method of identifying CDR3 regions in T-Cell receptor and/or immunoglobulin sequences, the method comprising:

-   -   (a) identifying a V gene segment comprised in the immunoglobulin         sequence by aligning the immunoglobulin sequence to a library of         known V gene segment sequences;     -   (b) identifying a J gene segment comprised in the immunoglobulin         sequence by aligning the immunoglobulin sequence to a library of         known J gene segment sequences;     -   (c) if V and J gene segments are identified, then comparing the         immunoglobulin sequence to a library of known CDR3 regions of         T-Cell receptor and/or immunoglobulin sequences to identify any         CDR3 region in the immunoglobulin sequence.

Alternatively, step (c) may be if V and J gene segments are identified, then searching the immunoglobulin sequence for flanking invariable anchor sequences to define the intervening T-Cell receptor and/or immunoglobulin CDR3 sequences.

In some embodiments, wherein steps (a) and (b) are performed using the Burrows-Wheeler Alignment or other sequence alignment algorithm.

In some embodiments, wherein if a CDR3 region is identified in step (c), then the method further comprises determining whether the identified V and J gene segments could be rearranged in the same locus using a heuristic approach.

In some embodiments, wherein if a CDR3 region is not identified in step (c), then the method further comprises determining if a combination of V(D)J gene segments is present based on Smith Waterman Alignment scores.

In an aspect, there is provided, a method for characterizing the immune repertoire of a subject, the immune repertoire comprising the subject's T-Cell population, the method comprising any of the hybrid capture methods described herein, any of the algorithmic methods described herein, or any combination thereof.

Any of the methods described herein may be used to capture a population of T-Cell receptor sequences, for immunologically classifying a population of T-Cell receptor sequences or for identifying CDR3 regions in T-Cell receptor.

In an aspect, the methods described herein are for characterizing T-cell clonality for a disease in the subject.

In some embodiments, the T-Cell receptor sequences are from tumour infiltrating lymphocytes.

In an aspect, the methods described herein are for identifying therapeutic tumour infiltrating lymphocytes for the purposes of expansion and reinfusion into a patient and/or adoptive cell transfer immunotherapy.

In an aspect, the methods described herein are for monitoring T-cell populations/turnover in a subject, preferably a subject with cancer during cancer therapy, preferably immunotherapy.

In an aspect, the methods described herein are for characterizing the immune repertoire of a subject, the immune repertoire comprising the subject's B-Cell population.

In an aspect, the methods described herein are for capturing a population of B-Cell receptor sequences with variable regions within a patient sample, for immunologically classifying a population of B-Cell receptor sequences, or for identifying CDR3 regions in B-Cell receptor sequences.

In an aspect, the methods described herein are for characterizing B-cell clonality as a feature of a disease in the subject.

The present methods may be used in subjects who have cancer. Cancers include adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain/cns tumors, breast cancer, castleman disease, cervical cancer, colon/rectum cancer, endometrial cancer, esophagus cancer, ewing family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (gist), gestational trophoblastic disease, hodgkin disease, kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leukemia (acute lymphocytic, acute myeloid, chronic lymphocytic, chronic myeloid, chronic myelomonocytic), liver cancer, lung cancer (non-small cell, small cell, lung carcinoid tumor), lymphoma, lymphoma of the skin, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-hodgkin lymphoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma—adult soft tissue cancer, skin cancer (basal and squamous cell, melanoma, merkel cell), small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, waldenstrom macroglobulinemia, and wilms tumor.

In embodiments relating to T-cells, the subject may have a T-cell related disease, such as a T-cell lymphoma.

T-cell lymphomas are types of lymphoma affecting T cells, and can include peripheral T-cell lymphoma not otherwise specified, extranodal T cell lymphoma, cutaneous T cell lymphoma, including Sezary syndrome and Mycosis fungoides, anaplastic large cell lymphoma, angioimmunoblastic T cell lymphoma, adult T-cell Leukemia/Lymphoma (ATLL), blastic NK-cell Lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta T-cell Lymphoma, lymphoblastic Lymphoma, nasal NKIT-cell Lymphomas, treatment-related T-cell lymphomas.

In other embodiments relating to B-cells, the subject may have a B-cell related disease, plasma cell disorder, preferably a B-cell lymphoma. B-cell are types of lymphoma affecting B cells and can include, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone B-cell lymphoma (MZL) or mucosa-associated lymphatic tissue lymphoma (MALT), small lymphocytic lymphoma (also known as chronic lymphocytic leukemia, CLL), mantle cell lymphoma (MCL), DLBCL variants or sub-types of primary mediastinal (thymic) large B cell lymphoma, T cell/histiocyte-rich large B-cell lymphoma, primary cutaneous diffuse large B-cell lymphoma, leg type (Primary cutaneous DLBCL, leg type), EBV positive diffuse large B-cell lymphoma of the elderly, diffuse large B-cell lymphoma associated with inflammation, Burkitt's lymphoma, lymphoplasmacytic lymphoma, which may manifest as Waldenstrom's macroglobulinemia, nodal marginal zone B cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, primary central nervous system lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman's disease, B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, AIDS-related lymphoma, classic Hodgkin's lymphoma and nodular lymphocyte predominant Hodgkin's lymphoma.

In an aspect, the methods described herein are for identifying therapeutic B-cells for the purposes of expansion and reinfusion into a patient.

In an aspect, the methods described herein are for monitoring B-cell populations/tumover in a subject, preferably a subject with cancer during cancer therapy, preferably immunotherapy.

In an aspect, the methods described herein are for detecting minimal residual disease, whereby TCR or immunoglobulin rearrangements may be used as a marker of disease.

In an aspect, there is provided a library of probes comprising the depletion probes in Table D or at least one of the V-gene and J-gene probes set forth in any of Tables 2.1, 4, B1, or B2.

In some embodiments, the clonality analyses described herein may be performed serially.

In some embodiments, the clonality analyses described herein may be used to distinguish between samples.

The advantages of the present invention are further illustrated by the following examples. The examples and their particular details set forth herein are presented for illustration only and should not be construed as a limitation on the claims of the present invention.

Example 1

Methods and Materials

Assay Development

Several important theoretical considerations were entertained during the design phase of our novel sequencing-based TRGR assay (heretofore referred to as the NTRA).

Unlike the current BIOMED approach, we wished to avoid a gene-specific primer-based approach to signal amplification. To accomplish this, we chose a “hybrid capture” target enrichment approach by which input genomic DNA containing the TR genes might be enriched (or “captured”) relative to other segments of the genome. Several methodological approaches to target enrichment already exist, with multiple commercially available and rigorously optimized kits capable of enriching nearly any well-defined gene target(s)⁽⁴⁷⁻⁴⁸⁾.

The NTRA needed to be robust enough to accommodate sample types of variable DNA quality; this requirement reflects the clinical need to apply TRGR assays to a wide variety of specimens in a wide variety of contexts. Knowing that Formalin-fixed paraffin-embedded (FFPE) specimens typically contain degraded and often poor quality DNA (as such representing the “lowest common denominator” of specimen quality)⁽⁴⁹⁾, it was deemed necessary to specifically evaluate NTRA performance on FFPE specimens. Furthermore, the use of hybrid capture is also amenable to highly fragmented DNA specimens such as those from circulating cell-free DNA.

Likewise, the most useful NTRA should allow users to both accurately assess the “clonality” of an input sample (as can be done using BIOMED-2 based assays) but also fully characterize the clonotypes of constituent TRGR configurations. Thus it was essential that the NTRA not simply produce a binary “clonal” vs. “polyclonal” result but also provide a much more robust and quantitative data output, including the genes and CDR3 regions present within identified TRGR configurations.

We recognized that much of the utility of the NTRA would depend on the design of a robust bioinformatic analysis pipeline. Of note, at the time at which this project was undertaken, only a single widely-used pipeline existed (the International standard source for ImMunoGeneTics sequences & metadata (IMGT) V-QUEST system), mainly designed around 5′RACE PCR followed by Roche 454 sequencing⁽⁵¹⁾. As outlined below, several methodological and logistic motivations demanded a novel pipeline of our own design.

Current sequencing-based applications generally require that resultant sequence data (i.e. reads) be mapped to a reference (typically the genome of the organism of interest) using some form of alignment algorithm. Once this alignment is complete, secondary and tertiary tools are used to search for and catalogue sequence deviation from the reference. For our purposes, however, using the entire human genome as a reference map would be unnecessarily cumbersome, especially since the presence of closely juxtaposed V(D)J sequence within a single short (i.e. <500 basepairs (bp)) fragment of DNA is tantamount to evidence of TRGR. Furthermore, aligning to a single reference genome raises the informatics challenge of detecting gene rearrangements from a single alignment step. As such, a strategy of mapping sequence reads to only the reference genes in a parallel fashion (i.e. one mapping procedure to the V genes, and one separate mapping procedure to the J genes) was selected, along with an integrated TRGR detection algorithm

This strategy required the theoretical consideration that short sequence read input might result in excessive false negatives (i.e. artificially low TRGR detection rates). This problem might be mitigated, in theory at least, by ensuring that input DNA fragment lengths (and the resulting sequencing read lengths) are carefully set to within a reasonable range of sensitivity for the detection of TRGR in a given sequence. Since all possible TRGRs are combinatorially vast, this process could only be simulated using, for our purposes, an artificial test set of simply-concatenated sequences of all catalogued V, D, and J genes (a test set numbering 197400). By evaluating k-mer subsequences over a range of lengths (k), centred (without loss of generality) about the median of each artificial junction, an estimate of the sensitivity of TRGR detection for variable sequencing windows can be produced. This sequencing window can then be used as an “evidence-based” DNA insert length.

Insert Length Simulation

Appendix 2.0 outlines a MATLAB script designed to estimate the optimal DNA insert length (a value also generalizable to optimal shearing length and minimal Paired-end rEAd mergeR (PEAR)-assembled sequencing length) for the purposes of the NTRA. This optimum is subject to an important restriction: for our purposes, using the Illumina NextSeq platform, read lengths are limited to paired-ended reads of 150 bp each—this translates to <300 bp read lengths when paired-ends are joined by overlapping sequence (using, in our case, the PEAR algorithm⁽⁵²⁾).

Briefly, the code produces a simulation read set of all possible combinations of V-D-J sequences by way of simple concatenation (with the caveat that a much larger diversity of sequence is found in nature stemming from alterations of junctional sequence by way of splicing inconsistencies); next, the algorithm selects a k-mer (of length from k=32 to 302, in intervals of 30 bp) from within each simulation sequence; the resulting k-mer (centred, without loss of generality, at the junction median) is then subject to Burrows-Wheeler Alignment algorithm (BWA) alignment against the known reference V and J genes (as in the TRSeq pipeline) to evaluate how well the k-mers of each of the artificial reads can be mapped to both V and J genes (representing bioinformatic identification of TRGR within the sequence in question). A histogram of percent detection vs. read length was then produced; analysis of those artificial V-D-J read combinations that could be reliably detected was also performed.

DNA Probe Design

We began by reviewing the sequence and metadata of all reference TR genes obtained by way of a (FASTA-formatted) data download from the IMGT database. All sequences were subjected to a series of Clustal W⁽⁵³⁾ alignment analyses to verify that sequence alignment was limited to known reference motifs (i.e. the J-gene F/W-G-X-G motif and V-gene conserved Cysteine⁽⁵⁴⁾) and to allele-to-allele overlap.

DNA probe design was then performed using the IMGT reference sequences (including all annotated V and J gene functional, pseudogene and open reading frame sequences) using the xGen Lockdown probe technology. Briefly, this technology is a hybrid-capture-based technology by which biotin-tagged DNA probes (complementary to known sequences/genomic regions set at a 1× depth of coverage) are allowed to hybridize with sample DNA, followed by a streptavidin elution procedure performed to enrich the target sequences⁽⁴⁰⁻⁴³⁾.

In line with previous studies employing xGen Lockdown probes⁽⁴⁰⁻⁴³⁾, each DNA probe was designed to a length as close to 100 bp as possible. Using the IMGT database, germline-configuration sequences were extracted for all alleles of all J-genes, with additional leading and trailing IMGT nucleotides added (as necessary) to obtain 100 bp probe lengths; for those instances in which the IMGT data was insufficient to prepare 100 bp probes, additional random nucleotides were added to the leading and trailing ends of the available sequences. Again using the IMGT database, germline-configuration sequences were extracted for all alleles of all V-genes, with additional leading and trailing IMGT nucleotides added to ensure that the 5′ and 3′ ends of the germline-configuration genes were covered by a given probe (this design, it was theorized, would be able to account for gene re-arrangement at either end of a V-gene, regardless of strandedness, while still covering the vast majority of the sequence of each gene/allele). With careful placement of the probes as outlined above, we hoped that this design would also limit any specific stoichiometric bias among the V-genes represented in the target pool.

Table 2.1 outlines the complete list of xGen Lockdown probe design sequences (with relevant associated metadata).

NTRA Work-Flow

The NTRA work-flow is summarized in FIGS. 1 and 5. Briefly, the process begins with DNA isolation, performed for the purposes of this study according to the protocol of Appendix 2.1. Isolated DNA was retrieved from frozen archives and quantified using the Qubit assay, per Appendix 2.2. Input DNA was shorn using a Covaris sonicator (Appendix 2.3) set to a desired mean DNA length of 200 base pairs; adequate shearing was confirmed using TapeStation assessment. Sequence libraries for each specimen were prepared using the protocol outlined in Appendix 2.4; multiplexing was accommodated using either TruSeq or NEXTflex-96 indices (the latter employed in the final validation run to permit large-scale multiplexing). Library preparation results were validated relative to input short DNA using TapeStation assessment. Subsequently, hybrid-capture with the above described xGen Lockdown probes was performed; captures were performed in pools of 9-13 input libraries, based on a pre-calculated balance of input DNA. The captured library fragments were then repeat-amplified, followed by final Qubit and TapeStation QC-steps. Finally, paired-end 150-bp sequencing was performed on the Illumina NextSeq platform using either a mid- or high-output kit (depending on sample throughput), according to the manufacturer's instructions (Appendix 2.5). The resulting read-pair zipped FASTQ-formatted data files were de-compressed and merged using the publically available PEAR alignment algorithm using a minimum of 25 bp overlap; this allowed the 150-bp sequencing maximum to be expanded to at least 200 bp, as suggest by the results of Section 2.1.2. Non-paired results were also tallied as a means of quality assurance. Subsequent analyses were performed using the custom-designed TRSeq analysis pipeline, as described below.

NTRA Data Analysis: The TRSeq Pipeline

The NTRA TRSeq pipeline was designed around three main algorithmic steps. The first performs local alignment indexed to the TR V and J genes implemented using the Burrows-Wheeler-Alignment (BWA) algorithm (5). From this algorithm, two important results are obtained: the first is a “reads-on-target” estimate (since the genes enriched for (i.e. the TR V and J genes) are those genes used as the index reference gene set); second, by way of the resulting Sequence Alignment Map (SAM) file output, the original input reads are filtered to exclude those unlikely to contain any of the TR V or J genes. This latter step reduces the informatic burden of input to the (relatively computationally slow) second algorithm step (using either heuristics or the Smith-Waterman Alignment (SWA)). Of note, the BWA algorithm could be implemented on a UNIX-based platform only (s).

The second algorithm step is designed to extract CDR3 sequences wherever present. This algorithm was implemented in MATLAB, guided by previous publications (u), and using a regular-expression (regexp) based search algorithm.

The third step combined the above alignment and CDR3 data (where present), to decide whether a given read contains a TRGR. To do this, one of two decision approaches is used: if a CDR3 is identified in a read, a heuristic approach is employed to decide if the BWA-alignment reference genes could be rearranged within the same locus; the second, in the event that a CDR3 is not detected, relies on the SWA-determined alignment scores to determine if a given combination of V(D)J genes is present.

Bioinformatic Target Enrichment (Burrows-Wheeler-Alignment Algorithm)

Much like the technical aspects of the NTRA function to enrich TR genes at the DNA level, so too can an informatics target-enrichment approach be employed. Using the BWA algorithm⁽⁵⁵⁾, a series of FASTQ-formatted reads are first mapped relative to a reference index of IMGT TR V and J genes. Any reads containing sequence mapping to any of the reference genes are flagged as such in the SAM-formatted output file as mapped, whereas those not containing any TR V or J gene mapped sequence are assigned the SAM Flag 4. In this context, unmapped reads are unlikely to contain any detectable TR V(D)J gene rearrangements; this predicate is logical inasmuch as sufficient residual germline sequence of a TR V and/or J gene are required in a read to permit TRGR detection.

Reads-on-target and gene-coverage estimates are also derived using the BWA algorithm, since NTRA input probes consist only of TR V and J genes; this measure is calculated as a percentage of the number of unique reads mapped to the IMGT reference TR V and J gene indices relative to the total number of reads in the input FASTQ-formatted file.

CDR3 Sequence Extraction and SWA Alignment

This part of the TRSeq algorithm was implemented in MATLAB using strategies similar to those employed by the IMGT⁽⁵⁶⁻⁵⁸⁾. The IMGTN-QUEST system utilizes a CDR3 sequence extraction algorithm⁽⁵⁷⁻⁵⁹⁾ and an SWA⁽⁶⁰⁾ algorithm performed against the IMGT reference sequences; the IMGT algorithms are all implemented in JAVA and processing is performed on IMGT servers.

As highlighted previously, we were unable to rely solely on the IMGT system for informatics results for several reasons: (1) the export of patient sequence data to an external non-secured network can be risky if insufficiently censored identifying metadata are also included; (2) the IMGT/High V-Quest system has a 500,000 sequence input limit (which may be substantially less than the number of sequence reads that need to be analyzed in the run of even a single high-throughput sequencing run); and (3) the queueing used by the IMGT can be lengthy, requiring a wait of possibly several days for sequence interpretation to begin.

A MATLAB implementation was chosen for convenience, programming familiarity, and because of easy vectorization, parallel computation and object-oriented programming capabilities. In addition, the MATLAB programming and command-line environments are able to easily incorporate UNIX and PERL-based scripts, including the BWA^((Li, 2009)) and CIRCOS software⁽⁶¹⁾ suites, respectively.

The full coding of the analysis algorithm is presented in Appendix 2.6.2. The MATLAB code was written to accommodate FASTQ-formatted data, align each read using BWA to the reference TR V and J gene germline sequences, index the resultant data, test each indexed read for (and extract if present) a CDR3 sequence (using the uniformly present C-X(5 . . . 21)-F/W-G-X-G amino acid motif, per the IMGT canonical sequence motif^((2,63))), and perform either an heuristic or SWA alignment-based validation of the reads mapped by BWA as evidence of a rearrangement within the read in question.

The SWA algorithm produces an optimal local alignment^((60,64)) of two co-input sequences (in this case, a query sequence relative to an IMGT reference sequence), and provides an alignment score (a unit-less measure of the degree to which the alignment perfectly matches an input sequence to its co-input sequence). For the purpose of this instance of the algorithm, for any case in which multiple possible alignments were produced, the alphabetical highest-scoring alignment was selected as the “correct” alignment, provided that this score was at least greater than the minimum cut-off score.

The minimum SWA alignment cut-off score was empirically determined for each of the three V, D, and J-gene gene groups using a large set of confirmed-negative sequences evaluated using the IMGT/HighV-QUEST system^((56,57)). The MATLAB code required for implementation of this algorithm is outlined in Appendix 2.6.1. A “practice” set obtained from the IMGT database^((65,66)) was also employed to test the pipeline, consisting of IMGT PCR-confirmed TRGR sequences with known V-D-J combinations and CDR3 sequences (see Section 3.1.3 for results of this practice set analysis).

Analytical Validation

A selection of 10 “First-Run” samples formed the basis of the analytical validation. These samples included 6 de-identified actual patient samples, obtained from flow-sorted peripheral blood specimens, tumour-infiltrating lymphocyte populations or in vitro cultures of lymphocytes. These samples were each subjected to flow-cytometric evaluation and cell-counting for basic immunophenotyping and cell-input consistency. In addition, four cell lines with known and well-described TR gene rearrangements (based on references cited by the IMGT database⁽⁶⁷⁾) were also included (i.e. Jurkat (Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ) ACC-282), SUPT1 (American Type Culture Collection (ATCC) CRL-1942), CEM (ATCC CCL-119) and MOLT4 (ATCC CRL-1582)).

A three-part analytical validation approach was employed. First, the results obtainable by analysis of the sequencing data using the IMGT/High V-Quest pipeline were directly compared with the results of the TRSeq pipeline. Next, a PCR & Gel Electrophoresis experiment was designed to confirm the presence of the upper 90^(th) centile of rearrangement configurations. Finally, the predominant rearrangements with accompanying TRSeq-identified CDR3 sequences were further Sanger-sequenced to validate this latter component of the NTRA analysis.

Comparison with IMGT Results

Given the limited input size capacity of the IMGT/High V-Quest system, a read-by-read comparison of a 10% random subset of the NTRA sequencing data was performed. From the IMGT analysis, a read was assumed to contain evidence of a rearrangement when the IMGT pipeline Junction analysis yielded an in-frame result. In addition, a read-by-read comparison of the alignment results (by gene name, for all V, D and J genes) was also performed.

PCR & Gel Electrophoresis Validation

A PCR-based experiment was deemed a reasonable orthogonal validation approach, given the gold standard BIOMED-2 assay methodology. Knowing that the number of possible rearrangements detected by the NTRA might be substantially large, the PCR validation was arbitrarily limited to those TRSeq-detected rearrangements in the upper 90^(th) centile (i.e. percent rearrangement of greater than 10% of total rearrangements). Given this restriction, however, to ensure an adequate denominator of reactions for comparative purposes, all PCR validation experiments were uniformly performed across all 10 first-run samples.

PCR validation primer sets were constructed modeling the standard V-D-J orientation of rearranged TR genes; specifically, the PCR forward primer was set in the V gene and the reverse primer set in the anti-sense strand of the J gene. For each TRSeq-identified rearrangement above 10% of total rearrangements, the V and J genes were identified and the IMGT primer set database searched for gene (not allele) specific primers. While the IMGT primer database did contain a number of suggested primers, many of the TR genes did not have an available appertaining primer. As a result, where necessary, the anticipated rearrangement sequence (containing the V gene sequence artificially positioned before the J gene) was used to derive custom primers using the NCBI Primer-Blast tool⁽⁶⁸⁾. Careful attention was paid to ensure that each resulting theoretical PCR product length was at least 100 bp (the lower limit of fragment size reliably detectable by standard gel electrophoresis) and that a sufficient amount of the anticipated CDR3 region sequence would be preserved in the PCR product. In addition, the theoretical product length was recorded as an approximate size reference for analysis of the resulting electrophoresis migration patterns.

All putative primer pairs were then re-submitted to Primer-Blast⁽⁶⁸⁾ to assess for the possibility of non-specific products; the final set of putative primers pairs was also evaluated using the UCSC in silico PCR algorithm 0) to confirm that no germline configuration products of less than 4 kb might be produced. Primer set physicochemical characteristics were evaluated using the IDT OligoAnalyzer Tool (v 3.1); Clustal W (53 alignments were used to identify significant primer sequence overlaps (Clustal W alignments note significant overlap of the TRGJ1 and TRGJ2 primers. This overlap was considered acceptable in order to define which of the TRGJ1 and TRGJ2 genes were present (given the presence of 5′ end non-homology). Since the PCR/electrophoresis results suggested the presence of both TRGJ1 and TRGJ2 positive products, the dominant TRGJ1 primer was selected for subsequent analyses and the TRGJ2 results excluded). The final primer-set sequences are listed in Table 2.2.

Custom primer set production was performed commercially by IDT and the forward and reverse primers were then mixed according to the design outlined in Appendix 2.7.2. PCR was performed in a 384-well plate on an Applied Biosystems Veriti thermal cycler using the Thermo Scientific 2× ReddyMix PCR Master Mix kit according to the manufacturer's instructions; several control reactions were included, as highlighted in Appendix 2.7.2. Gel electrophoresis was performed in a 96-well Bio-Rad Sub-Cell Agarose Gel Electrophoresis System (necessitating 4 separate runs); electrophoretic migration was referenced against an Invitrogen Tracklt 1 kb DNA ladder and visualized using ethidium bromide fluorescence, photographed in a Alphalmager Gel Imaging System. Electropherograms were digitally rendered, adjusted and composited using Adobe Photoshop CC 2014. The resulting electrophoretic results were used in Receiver-Operating Characteristic (ROC) curve analyses relative to the corresponding TRSeq normalized read counts.

Sanger Sequencing Validation

Based on the results of the above PCR & Gel Electrophoresis experiment, rearrangement-positive PCR products were purified using a QIAquick Spin PCR purification kit (100 bp to 1 kb range) according to the manufacturer's instructions (Appendix 2.7.3). Purified PCR products were then quantified by Qubit and 20 ng equivalent aliquots were taken (with an additional volume reduction step using a SpeedVac, as required, for large volumes). The corresponding primer of the original primer pair with the lowest melting point was then selected for the purposes of single-direction Sanger Sequencing (performed at the TCGA Sick Kids Hospital Sequencing Facility).

The resulting sequencing results were analyzed using the FinchTV v 1.4 software suite, with corrections to sequencing error and reverse-complement sequence corrections performed manually as required. The originating TRSeq CDR3 sequences were then compared to the “reference” Sanger Sequence result. This comparison was performed in two ways: first, a basic multi-alignment comparison was performed (using the multialign algorithm of the MATLAB Bioinformatics Toolbox); second, a k-mer based PHRED-quality adjusted comparison was performed.

For the k-mer based approach, for a given V and J gene configuration, the most frequently detected TRSeq CDR3 sequences were aligned to the corresponding Sanger Sequencing result. In this context the Sanger Sequencing results were taken to represent a “consensus” of sequence data produced over all possible V and J configuration CDR3 sequences for that V-J gene configuration (reflecting the possibility of variable TRGR subclones). As such, in order to adjust the Sanger sequencing results to account for the potential alignment of a non-dominant subclone, a quality-based alignment algorithm was employed, based on the methods of⁽⁷⁰⁾ Each input TRSeq CDR3 sequence was aligned along a progressive series of k-mers of the Sanger sequence using a custom quality-based alignment algorithm (code outlined in Appendix 2.8). For each alignment result, if the optimal alignment score occurred within the expected sequencing region (thereby representing an optimal alignment within a region of Sanger sequence expected to contain the actual CDR3 based on flanking primer sets), as outlined in Table 3.1A, the CDR3 sequence was classified as correct (and vice-versa). This classification was then used to perform ROC analysis to determine what number of TRSeq CDR3 sequence read counts might be considered a validated cut-off.

Coverage Analysis

In addition to the above validation results, more detailed assessment of NTRA technical performance was also performed. Specifically, given that the NTRA relies on target enrichment, an assessment of the gene coverage of the NTRA was required. In addition, given that much of the utility of the NTRA might relate to identifying clonal cell populations, it was necessary to assess the dynamic sensitivity of the NTRA to decreasing numbers of cells bearing specific TR gene rearrangement configurations and, conversely, assess how standardized read counts might correlate with approximate input cell numbers.

Coverage Dynamics by Specimen Clonality

Given the nature of TRGR, by which genomic components are excised upon rearrangement, we evaluated the coverage dynamics across the first-run specimens. This analysis served not only as a mean of qualitatively comparing how V and J gene coverage might be expected to vary in specific types of specimens, but also to evaluate which coverage metrics might be most predictive of specimen type (i.e. clonal vs not) and what specific cut-off criteria might be used to this effect. To do this, ROC-based analyses of mean overall and locus-specific coverage data for V and J genes was performed, as well as percent genes at least 100× for each of V and J gene types.

Negative Control Coverage Assessment

For the purposes of this project, a fully germline TR gene configuration was approximated using a cell lines of embryonic origin and a cell line that has been fully sequenced without any known/reported TR gene derangements. The former scenario was approximated using the HEK293 cell line (an embryonic kidney cell line; ATCC CRL-1573) and the latter using a Coriell cell line (whose genome has been well-characterized and is not known to contain TR rearrangements). Use of the latter cell line was incorporated given that, in our hands, this cell line had been previously and purposefully degraded by FFPE treatment, representing a scenario of TR gene coverage assessment in the context of degraded DNA.

Total genomic DNA was extracted from previously cultured HEK293 cells and FFPE treated Coriell cell cultures and subsequently subjected to the NTRA, as outlined in Appendices 2.1 to 2.5. Standard TRSeq analyses were performed for each sample, with special deference paid to the coverage results.

Dilution Series

A rigorous dilution series experiment, in the context of this project, might involve a flow-sort spike of cells with a known TR gene configuration into a population previously determined to be “polyclonal”; this might be approximated, for example, using a well-characterized cell line spiked into a population of lymphocytes obtained from normal blood. Rather than undertaking this more complex and expensive approach, an approximation of this dilution experiment was undertaken with DNA obtained from the Jurkat cell line spiked into a known-polyclonal lymphocyte population DNA isolate (the A037 sample; see Results section 3.2). Specifically, Jurkat DNA was spiked in at log-decrements (as outlined in Table 2.3) based on a lymphocyte total DNA complement assumed to be 0.7 pg, given the results of previous publications (71-7). The total DNA of each sample in the dilution series was verified (and compared to expected values) using a Qubit assay; the samples were then subjected to the NTRA, as outlined in Appendices 2.1 to 2.5. Standard TRSeq analyses were performed, with special deference to changes in the raw read counts of Jurkat-specific TRGR configurations across the dilution series.

Alternative Method and Algorithm

Hybrid-Capture Protocol

For T cell receptor (TCR) diversity and clonality analyses we investigated genomic DNA isolated from flow sorted T cells isolated by affinity magnetic bead isolation, peripheral blood mononuclear cells (PBMC) isolated from blood by density gradient separation, cell-free plasma DNA extracted from blood, or scraped and pelleted immortalized cell lines.

Isolated DNA is sheared to ˜275 bp fragments by sonication in 130 uL volumes (Covaris). DNA libraries are generated for illumina platform sequencing from 100-1000 ng of sheared DNA by ligation of sequencing library adaptors (NextFlex) using the KAPA library preparation kit with standard conditions. Libraries are visually assessed (Agilent TapeStation) and quantified (Qubit) for quality.

Hybridization with probes specifically targeting the V and J genes is performed under standard SeqCap (Roche) conditions with xGen blocking oligos (IDT) and human cot-1 blocking DNA (Invitrogen). Hybridization is performed either at 65 C overnight. The target capture panel consists of 598 probes (IDT) targeting the 3′ and 5′ 100 bp of all TCR V gene regions, and 95 probes targeting the 5′ 100 bp of all TCR J gene regions as annotated by IMGT (four loci, 1.8 Mb, total targeted 36 kb). Hybridization and capture can be performed as a single step with a combined V/J panel, as a single step with only the V panel, or as a three step process when non-rearranged fragment depletion is desired consisting of a V capture, then depletion, then J capture.

For depletion of non-rearranged fragments 500 ng-1000 ng of library is depleted by hybridization with a panel of 137 probes (IDT) targeting the 5′ 120 bp of selected TCR V gene region 3′ untranslated regions as annotated by IMGT (four loci, 1.8 Mb, total targeted 16.5 kb) and 131 probes (IDT) targeting the 5′ 120 bp of selected Ig V gene region 3′ untranslated regions as annotated by IMGT (three loci, 3.1 Mb, total targeted 15.7 kb). A modified and truncated SeqCap protocol is employed wherein following incubation with M-270 streptavidin linked magnetic beads (Invitrogen), the hybridization reaction is diluted with wash buffer I, beads are discarded and the supernatant is cleaned up by standard Agencourt AMPure XP SPRI bead purification (Beckman).

Algorithm

A custom Bash/Python/R pipeline is employed for analysis of paired read sequencing data generated by Illumina NextSeq 2500 instrument from the hybrid-capture products. Referring to FIG. 5, this pipeline consists of four major steps: (1) Merging of the paired reads; (2) Identification of specific V, J, and D genes within the fragment sequence; (3) identification of the V/J junction position as well as the antigen specificity determining Complementarity Determining Region 3 (CDR3) sequence at this site; (4) Calculation and visualization of capture efficiency and clone frequency within and across individual samples.

(1) 150 bp paired-end reads are merged using PEAR 0.9.6 with a 25 bp overlap parameter. This results in an approximate 275 bp sequence for each fragment and enhances the sensitivity of V,J,D gene detection using the subsequent search strategies.

(2) Individual BLAST databases are created using all annotated V, D, J gene segments from IMGT. These full-length gene sequences are the targets of the hybrid-capture probe panel. Individual merged reads are iteratively aligned using BLASTn with an e value cut-off of 1 to the V database, J database then D database with word size of 5 for D segment queries. Trimming of identified V or J segments in the query sequence is performed prior to subsequent alignment to reduce false positives and increase specificity, particularly for the D gene query.

(3) In order to identify CDR3 sequences, the V/J junction position is extracted from the previous search data for those fragments containing both a V and J search result 80 bp of DNA sequence flanking this junction is translated to amino acid sequence in all six open reading frames and sequences lacking stop codons are searched for invariable anchor residues using regular expressions specific for each TCR class as determined by sequence alignments of polyclonal hybrid-captured data from a healthy patient as well as TCR polypeptides annotated by IMGT.

(4) Calculation of capture efficiency (on-target/off-target capture ratio) is performed by aligning all recovered, merged reads to the human genome (BWA) and dividing the number of reads aligning to the TCR loci by the total number of reads. The total number of unique TCR clones is determined by finding the unique minimum set of V/J combinations and the number of occurrences of each is tabulated. This data is visualized using R as stacked bar charts to generate figures that can be quickly visually assessed on a sample-by-sample basis for monoclonal or polyclonal signatures or clinically relevant enrichment of particular clones.

Application of the Algorithm to Existing Sequencing Data

The custom pipeline is not dependent on our hybrid-capture protocol and can be performed on non-target captured whole genome or RNA-seq data. In this situation, an in silico capture is performed by extracting reads aligning to the four TCR loci (7:38250000-38450000, 7:141950000-142550000, 14:22000000-23100000) or Ig loci (chr2:89,100,000-90,350,000, chr14:106,400,000-107,300,000, chr22:22,350,000-23,300,000) from DNA (BWA) or RNA (STAR) sequence data (SamTools), followed by paired-end nucleotide sequencing data extraction (PicardTools). These reads are then inserted in to the previously described computational pipeline.

Results and Discussion

Informatics

Insert Length Simulation

FIG. 3-1 details the DNA Insert Length Simulation results. The analysis suggested a plateau of sensitivity of greater than 99.1% reached after 182 bp. For convenience, an adequately “evidence-based” insert length and informatics read length goal of 200 bp was chosen for the NTRA.

After further analysis excluded extra-locus V-D-J gene combinations (i.e. combinations not likely to result from rearrangements within the same TR locus), the number of missed combinations was reduced from 1752 to 80.

From among the above 80 intra-locus combinations, missed rearrangements originated only from among the TRB and TRG loci, with particular enrichment of TRBV6-2*01 and TRBV6-3*01 within the former (65 of 80) and enrichment of the TRGJ1*02 within the latter (15 of 80).

Analysis by phylogenetic sequence alignment (using the SWA alignment algorithm) within the TRBV6 group showed significant cophenetic linkage between the TRBV6-2*01 and TRBV6-3*01 genes (data not shown). Similarly, analysis by phylogenetic sequence alignment within the TRGJ gene group suggested significant cophenetic linkage between TRGJ1*02 and TRGJ2*01 (data not shown). These results suggest that combinations within the artificial read set involving either of these TRBV genes were likely misaligned to another TRBV gene (likely the next closest cophenetic “cousin,” TRBV6-2*02) and that the TRGJ1*02 gene was likely misaligned to the TRGJ1*01 gene. Of note, the observation of closer cophenetic linkage between TRBV6-2*01 and TRBV6-3*01 rather than between TRBV6-2*01 and TRBV6-2*02 (as would be expected for two alleles of the same TR gene) and of closer cophenetic linkage between TRGJ1*02 and TRGJ2*01 rather than between TRGJ1*01 and TRGJ1*02, suggests error on the part of the IMGT classification.

MATLAB SWA Score Cut-Off Determination

The results of the empirical V, D and J-gene MATLAB alignment score cut-off score experiment are presented in FIG. 3-2. This experiment employed the code presented in Appendix 2.6.1 run on a test set of 91375 Illumina sequencing reads obtained from anonymized myeloid leukemia samples enriched for sequences outside of the IG/TR loci. These sequences were “confirmed” negative for V, D, and J gene sequences using the IMGT/High V-QUEST system (Brochet et al., 2008; Giudicelli et al., 2011). Given an experimental number of sequencing reads of at least 1 million, a 6-sigma cut-off score for MATLAB TRSeq analysis suggests 53.23 for the V genes; 19.02 for the D genes; and 34.43 for the J genes. It is easily observed that the cut-off values increase respectively from D, to J, to V genes; this observation parallels the mean length of the reference sequences from D to J to V genes.

TRSeq Analysis of IMGT-Produced TRGR Sample Sequence Reads

A sample of 268 short read sequences was downloaded from the IMGT website. These sequences consist of a variety of previously characterized TR and IG gene rearrangements available for download in FASTA format. After re-formatting into FASTQ format (using arbitrary quality scores), the dataset was analyzed using the TRSeq pipeline. Of the 268 short read sequences, 55 were identified by the IMGT as containing TR genes (either V or J genes); to these reads, there was perfect (100%) TRSeq alignment concordance, both in relation to gene name and allele. The TRSeq algorithm identified 50 of the 55 reads as containing evidence of TRGR; the 5 remaining reads were identified by the IMGT as containing rearrangements within the TRD locus, each with a TRSeq CDR3 region correctly identified. These results suggest that the 5 TRSeq “false-negatives” were informatically rejected by the TRSeq algorithm based on insufficient TRD D-gene SWA alignment score values; this form of error is not alarming given the more stringent means by which the TRSeq SWA alignment score cut-off values were determined relative to the IMGT/High V-QUEST pipeline^((56,58)).

First-Run Results Summary

Table 2.5 outlines the flow-cytometric features of the 6 patient lymphocyte samples. These immunophenotypic features were in keeping with the lymphocyte sample sources of origin (also documented in Table 2.5), varying from normal patient peripheral blood mononuclear cells to highly immuno-sensitized lymphocyte cultures from tumour infiltrating lymphocyte specimens. Notably, the A037 sample served as a model of a “polyclonal” lymphocyte population whereas, for the purposes of qualitative assessment at least, the L2D8 sample could be immunophenotypically interpreted as highly “clonal” in nature.

In addition, model “clonal” samples were included, consisting of the Jurkat, CEM, SUPT1 and MOLT4 cell lines. Table 2.6 lists the previously documented rearrangements, as cited in the IMGT database⁽⁶⁷⁾.

Prior to target enrichment and sequencing, adequate quality control was assured, as documented by pre and post-library preparation TapeStation tracings (see FIG. 3-3). Post-target enrichment quality control was assured in the same manner.

Illumina NextSeq sequencing was then performed on Tapestation-normalized pooled input target-enriched DNA. The appertaining read-pair FASTQ-formatted zipped files were decompressed and the PEAR paired-end merging algorithm was run with a minimum strand sequence overlap of 25 bp. A breakdown of the PEAR results is shown in FIG. 3-4. The resulting PEAR-merged FASTQ-formatted read files were input to the TRSeq pipeline.

FIGS. 3-5, 3-6, and 4 summarize the TRSeq metadata for the first-run sample series, including input reads, reads-on-target, summary coverage statistics, and a histogram of read counts for the proportion of each locus contributing to identified TRGR's, respectively.

One important highlight is the variation in coverage seen across the 10 specimens relating to the D locus. As described in the introduction, since the D locus genes are sandwiched within the larger A locus, the D locus genes are often deleted upon A locus rearrangement. The coverage profiles of the D locus therefore paralleled this phenomenon with lower D locus coverage identified in the clearly clonal or oligoclonal samples relative to the polyclonal samples (e.g. L2D8 and cell line samples vs. A037 peripheral blood sample).

FIGS. 3-7A and 3-7B display composites of the circos plots obtained from the 10 first-run samples. Much as the coverage profiles differed across the samples (as seen in FIGS. 3-7C & 3-7D), the resulting circos plots demonstrated a clear aesthetic difference from polyclonal to clonal/oligoclonal samples, with emphasis on the number and relative width of the composite circos links (i.e. fewer and broader in width in the more clonal cases and vice versa). Also of note, the color distributions were distinctly different with the more polyclonal cases, containing a larger number of smaller-quantity “subclones” involving a more disparate number of TR genes.

Analytical Validation

IMGT/High V-Quest Comparison

The boxplots of FIG. 3-8 summarize the comparison of the IMGT/High V-Quest pipeline analysis to the TRSeq results. The degree of concordance of read-to-read interpretation with respect to identifiable rearrangements (as present or not identified) is excellent (99%), as is the degree of concordance of named D genes (99%). A lower degree of concordance is noted for named V and J genes (68% and 84%, respectively). These results may relate to different initial alignment algorithms employed, as well as different gene-identity cut-off values employed in the SWA algorithms of the IMGT/High V-Quest and TRSeq pipelines. In light of the results seen in Section 3.1.1, the possibility of V and J gene phylogenetic sequence misclassification in the publically-available IMGT sequence databases should also be considered as a possible contributing factor.

The high D-gene concordance relative to the V and J-gene values may relate to both the shorter reference sequences of the D-genes relative to the V and J genes, as well as the lower number of reference D-genes available for rearrangement. It is important to point out the possibility of a theoretical bias against D-gene identification in input reads, given that TRGR reads containing D-genes require 3 rather than 2 composite genes, which could be more difficult to detect in the context of restricted average read lengths. This consideration was brought to bear during the NTRA assay design phase (as described in Section 3.1.1), with the conclusion that adequate flanking 5′ and 3′ sequence would be available on average in the scenario of read input length of 200 bp or more to reliably identify reads containing V-D-J rearrangements.

PCR & Gel Electrophoresis

PCR primers were mixed and the results by Agarose gel electrophoresis are shown in FIG. 3-9. Note that results obtained from PCR reactions using the TRGJ2 reverse primer are excluded, as noted in Section 2.2.2. Two classification approaches may then be entertained, one based on dark-staining PCR bands only, and the other based on any staining (assuming bands to be of appropriate molecular weights, as set out in Table 3.1A). When these classifiers are compared with the read-count-normalized results of the TRSeq algorithm (as set out in Table 3.1A), the ROC curves of FIGS. 3-10A & 3-10B are obtained, respectively. In the former scenario, the ROC Area-Under-the-Curve (AUC)=0.91 and p-value <0.001, with a TRSeq normalized read count of 6.7 or more. Based on the results of FIG. 3-10B, a less stringent classification results in a reduced AUC=0.71 and p-value <0.001, with a TRSeq normalized read count of 1.7 or more.

Sanger Sequencing Results

PCR reactions that were post-PCR purified were submitted for Sanger Sequencing. FIG. 3-11 denotes the alignment of each corresponding TRSeq CDR3 sequence (and associated raw read count) in relation to the manually-verified/corrected Sanger Sequencing Result; only those Sanger Sequencing specimens containing TRSeq-identified CDR3 regions, those of sufficient quality for interpretation, and those not rejected based on use of the TRGJ2 reverse primer were further considered.

As may be seen in FIG. 3-11, there appears to be a trend for each distinct primer configuration inasmuch as TRSeq-identified CDR3 sequence configurations having sufficient associated read counts, as suggested from Section 3.3.2, show the best contiguous alignments to the corresponding “reference” Sanger Sequences.

To better quantify this relationship, we utilized a k-mer based quality-score adjusted alignment analysis. For each relevant primer configuration, the corresponding CDR3 was aligned using PHRED-based quality-score adjustment across the length of the Sanger “reference” sequence. If the optimal alignment from this process was present within the sequence window in which a CDR3 was theoretically predicted to exist, the CDR3 read configuration was classified as “compatible.” The resulting classification analysis is represented by the ROC curve of FIG. 3-12 (AUC=0.832, p-value=0.006). Based on this analysis, the optimal TRSeq normalized read count cut-off is 4.9.

Coverage Analysis

Coverage Dynamics by Specimen Clonality

Using the qualitative data of Table 2.5, specimens were classified as either “clonal” or “polyclonal.” The resulting ROC curves for the various coverage metrics were prepared (data not shown). Of note, a mean V-gene coverage assessment of the gamma locus appeared to suggest the highest non-unity AUC. Further, the ROC analysis suggested that a mean V-gene coverage of greater than/equal to 4366.4 showed optimal sensitivity and specificity (86% and 67%, respectively) for predicting whether a specimen was unlikely to be clonal. Care should be taken not to use these cut-off points without additional validation, however, given the low number of data points constituting the analysis. Rather, these data stand to suggest a need for further evaluation of the potential predictability of “clonal” status derived from coverage analysis within the gamma locus.

Negative Control Coverage Assessment

The NTRA was tested on samples of previously cultured HEK293 and Coriell cell lines; these analyses aimed mainly at estimating coverage ceilings for the NTRA, but also served as added negative control specimens (i.e. specimens known or expected not to contain any TRGRs).

Applying the PEAR algorithm⁽⁵²⁾ (with a minimum 25 bp forward-reverse read overlap) resulted in pairing of 83% of input reads in the HEK293 sample and 90% of input reads in the Coriell sample.

In both instances, the number of subsequently identified TRGR configurations did not meet the TRSeq cut-off criteria (TRGRs were identified in 0 of 5,729,205 total input reads in the HEK293 cell line and only 7 of 2,761,466 total input reads in the Coriell cell line). This was in keeping with the anticipated fully-germline configuration of each of these non-lymphoid origin cell types.

For the HEK293 cell line, the percent V and J genes at or above 100× coverage was 100%; the overall TR V gene coverage averaged 29960×; and the overall TR J gene coverage averaged 8789×.

For the Coriell cell line, the percent V and J genes at or above 100× coverage was 100%; the overall TR V gene coverage averaged 13379×; and the overall TR J gene coverage averaged 3925×.

Dilution Series

A dilution experiment was performed at log-reduction intervals, set up according to the design of Table 2.3, and adjusted according to Table 3.2 to account for Jurkat DNA concentration discrepancies. Three Jurkat cell line unique TRGR configurations were selected for inter-dilution comparison, namely the TRAV8-4-TRAJ3, TRGV11-TRGJ1 and TRGV8-TRGJ2 rearrangements identified & confirmed in Section 3.3. The above configurations were confirmed absent in the polyclonal (A037) sample. In addition, each of these configurations showed a specific dominant CDR3 sequence.

FIG. 3-13A details the mean of the raw read-counts (i.e. not normalized) across the three tracked V-J configurations (with error bars for standard deviation) vs. expected approximate Jurkat cell numbers (with adjustments for significant digits) from Table 3.2. An exponential trend line could be applied, with R-squared=0.9996.

Of note, when the extremum of the first dilution is excluded, the dilution curve is remarkably linear (as seen in FIG. 3-13B), but with a positive slope. This suggests a linear direct correspondence between read count and number of cells bearing a given V-J configuration at low levels.

In contrast to the reliable low-level detection by way of V-J configuration, detection narrowed to absolute clonotype (by including the CDR3 sequence) was limited to only the first three dilution specimens (i.e. sensitivity down to an approximated 1 in 125 cells; see FIG. 3-14).

This limited sensitivity speaks to the sensitivity of the TRSeq junction finder to sequencing error. Indeed, if even a single base is changed relative to the canonical regular expression required for detection of a CDR3 sequence, the junction finder will not identify the sequence correctly; likewise, any non-triplicate base insertion will not be detected as an in-frame CDR3 sequence. In contrast, since the TRSeq V and J gene enumeration scheme uses alignment-based algorithms, the TRSeq results relating to V and J gene enumeration are much more forgiving of higher the higher likelihood of sequencing error in clonotypes with low read counts, thus substantially improving the assay sensitivity for characteristically unique V-J gene configurations.

Support for these suppositions is echoed in part by previous work pertaining to core clonotype analyses⁽²⁷⁾. Indeed, when the proposed criteria of Bolotin, et. al.⁽²⁷⁾ for gathering low-level reads of similar but error-prone sequence into common core clonotypes are applied to the dilution experiment (implemented in Appendix 3), it is possible to identify reads comparable to the donotypes described above in even the most dilute samples.

For example, running the code of Appendix 3 with the input core clonotype of the TRGV8-TRGJ2 configuration, and allowing for a maximum of 3 sequence mismatches, 3 or more reads of satisfactory clonotype can be identified in dilutions 2-5. If the number of sequence mismatches is increased to 4, reads of satisfactory clonotype can be identified in all dilutions (i.e. down to an estimated sensitivity of 1 in 185646 cells).

The importance of these results stems from the applicability of this form of core clonotype analysis to a more accurate identification of minimal-residual disease, for example, at very low levels with remarkable sensitivity, even in the absence of traditional primer-directed sequence enrichment⁽⁷⁷⁾.

NTRA—BIOMED-2 Comparison

In keeping with the general approach used to assess BIOMED-2 results, the NTRA TRB and TRG clonotype tables were analyzed to compare the ratio of the dominant clonotype read count relative to the “background” read count. The largest read count not satisfying the normalized TRSeq read count according to the results of Section 3.3 was taken as the background read count value; alternatively, in the case where the dominant clonotype did not satisfy the normalized TRSeq read count cut-off of Section 3.3, the next largest clonotype read count was taken as “background”. From among each of the TRB and TRG loci, the largest dominant clonotype-to-background ratios were compared to the overall BIOMED-2 results using a ROC analysis.

See FIG. 3-15; the ROC analysis result could be classified as “good”⁽⁷⁸⁾ with AUC=0.82, p-value <0.001. Of note, this AUC value appears comparable to those observed in Section 3.3. Of even more impressive note is that the ROC-suggested dominant clonotype-to-background cut-off value was also comparable to that outlined in the current BIOMED-2 TRGR assay interpretation guidelines⁽⁷⁹⁾; indeed, the ROC analysis-suggested value of 3.4, which is effectively the median value of the “indeterminate” range of dominant peak-to-background ratios recommended for BIOMED-2 result interpretation⁽⁷⁹⁾.

Interestingly, when the above process was broken down into two separate comparisons of the TRB and TRG loci, the TRG locus was found to be the significant driver: the TRG locus comparison alone yielded a ROC AUC=0.81 (p-value <0.001) whereas the TRB locus comparison alone yielded a ROC AUC=0.60 (p-value=0.17).

NTRA Coverage Metrics—BIOMED-2 Comparison

As in Section 3.4, an analysis of coverage variation in relating to clonal status was undertaken (see also FIG. 3-16). In contrast to the results of Section 3.4, a far less significant series of areas-under-the-curve were observed from this analysis. The greatest AUC was noted by analysis of mean V-gene coverage (i.e. mean V-gene coverage over all four loci) with AUC=0.59, p-value=0.213.

Furthermore, the data from Section 3.4 suggested that analysis of coverage from the Gamma locus might be predictive of clonal status. Unfortunately, these hypotheses were not substantiated by way of the clinical validation set, from which the AUC for the TRG locus V-gene analysis and TRG locus J-gene analysis were 0.59 and 0.57, respectively.

The clear discordance between these results and those of Section 3.4 likely relates to several factors. First, the sample size in Section 3.4 is one-sixth that of the clinical validation set, making the results of Section 3.4 much more vulnerable to the effects of outliers. Second, the overall coverage in the analytical validation set was lower, owing to base-output restrictions using the mid-output NextSeq kit; as such, coverage correlations made in Section 3.4 might not necessarily be applicable to experiments performed using the high-output NextSeq kit. Thirdly, the clinical validation experiment was not subject to bias of assumption as to the clonality of each input specimen; rather clonality was specifically assayed using an orthogonal method.

SUMMARY

Described above is the first hybrid-capture-based T-cell clonality assay designed to assess clonality and provide clonotype data over all four T-cell gene loci. For this purpose, a custom MATLAB-based analysis pipeline was implemented using optimized object-oriented programming integrating the ultra-fast BWA alignment system and the aesthetically-pleasing circos-based genomic data visualization suite. The latter visualization was designed with current methods in mind, in which electropherographic plots serve as the primary means by which clonotypes are visualized.

Advantages of NTRA over traditional T-cell clonality testing assays Not only can the NTRA identify clonotypes from all four loci, the use of hybrid capture makes the process platform-agnostic. The laboratory work-flow can be integrated into any standard library preparation work-flow with the addition of a single hybridization step, capable of enriching for sequences containing T-cell genes of a several specimens at a time. In addition, as part of laboratory work-flows already using a hybrid-capture approach for other purposes, the probes used as part of the NTRA are amenable to “spike-in” combined hybridization reactions, provided that there is no significant probe-set sequence overlap or complementarity.

In comparison to the current BIOMED-2 based clonality assays, the NTRA adds a dearth of extra data, especially as pertaining to clonotype data from the gene-rich alpha-locus. This locus has traditionally been too diffusely distributed within the genome to be amenable to primer-based amplification, a challenge easily overcome using a hybrid-capture approach. Akin to the requirements of the IMGT, the NTRA outputs a clonotype table containing data specific to the best aligned allele. In contrast, however, visualized data is restricted to gene-level only, thereby providing a means of visualization comparable to electropherographic output. In addition, included with the latter, is the in-frame CDR3 sequence (where detected), data currently not available using either standard PCR-based techniques or the mainstream sequencing-based solutions (e.g. Invivoscribe).

In addition to validating the wet-bench and informatics using a number of orthogonal approaches, the NTRA was also shown to be theoretically sensitive to low-level clonotypes. This latter observation is an important boon to the hybrid-capture approach, suggesting that carefully performed hybrid-capture methods can provide signal amplification comparable to flow-cytometric⁽⁸¹⁾ and molecular approaches⁽³²⁾⁽⁸²⁾⁽³⁾.

Assay Cost & Efficiency Considerations

As highlighted in Section 3.8, the assay may be considered cost effective, depending on the specific scenario of interest. In addition, the use of a hybrid-capture approach allows for spike-ins of additional probes for other genomic regions of interest. This allows the possibility of running multiple assays from a single library preparation step, requiring only bioinformatic separation of the resulting enriched sequences.

Applications

Assessment of lymphocyte clonality is integral to the diagnosis of diseases and cancer affecting the immune system. In addition, sequencing of the T-cell repertoire of a patient has gained clinical value with the recent understanding of T-cell mediated recognition and destruction of neoplasms. Further, the development of adoptive cell therapy and recombinatorial engineering of T-cell receptors requires high-throughput molecular characterization of in vitro T-cell populations before transplant. PCR-based methods such as BIOMED-2 and Immunoseq are currently in use for TCR characterization however their costs and complexity remain barriers for clinical deployment requiring high-throughput multi-patient, multi-sample work-flows at low cost. We have therefore developed a hybrid-capture-based method that recovers rearranged TCR sequences of heavy and light TCR chains from all four classes in one tube per sample at low cost. TCR clonality and CDR3 prevalence can be rapidly assessed in a three-day turn-around time with an automated pipeline generating summary figures that can be rapidly assessed by clinicians.

Adaptive T-cell immunotherapy has become a field of great interest in the treatment of multiple solid-tumor cancer types. Non-childhood cancers, particularly those linked to chronic exposure of known carcinogens, are driven by the accumulation of mutations. Some of these mutations drive pro-tumorigenic changes, while others result in non-tumorigenic changes to proteins expressed by the carrier cell. During normal protein turnover these modified proteins are broken down in to short polypeptides and make their way to the surface of the cell in association with molecular surveillance molecules (MHC I). In this context these modified polypeptides are recognized as foreign neo-antigens by the host immune system, and in the context of other signals, lead to the activation of T-cells that direct the destruction of cells expressing these modified proteins.

It is now understood that many solid-tumours exist in a state where their presence recruits neo-antigen specific T-cell lymphocytes to the margins however further advance and effective destruction of the tumor is prevented by expression of checkpoint inhibition molecules on the tumor cell surfaces. Therefore immunotherapy has become a major area of advance in cancer therapy wherein such checkpoint inhibition molecules are masked through transfusion of antibodies. This allows recognition of tumor and its destruction by neo-antigen specific T cells. In order to further enhance such anti-tumor activity, tumor infiltrating lymphocytes (TIL) can be isolated from tumor biopsies and expanded in vitro, followed by subsequent transfusion in great numbers back in to the patient following immunodepletion to enhance transplant colonization thereby driving a durable antitumor response.

T-cell lymphocytes are fundamental to this process, however due to their exquisite specificity, only neo-antigen specific T-cells are capable of driving anti-tumor activity. As a result there is a need for molecular characterization of circulating T-cells in the patient before and after treatment, infiltrating T-cells in the tumor before and after treatment, and screening of expanded populations in vitro for safety and efficacy. Our method provides a high-throughput, low cost and rapid turn-around method for T-cell receptor characterization in order to facilitate clinical deployment and uptake of adoptive cell transfer immunotherapy.

This method is not only of use in immunotherapy applications, as any disease involving expansion of T-cell clones would benefit from its use. The symptoms of autoimmune diseases are driven largely by T-cell mediated cytotoxicity of “self” tissue and therefore the identification and expansion of specific T-cell clones can be monitored using this method. This method would also be useful to follow immune challenges such as infection or immunization in the development of anti-infectives or vaccines.

Example 2

There is also described herein a laboratory and bioinformatic workflow for targeted hybrid-capture enrichment of T-cell receptor loci followed by Illumina sequencing to assess the clonality of a range of specimens with variable T-cell clonal complexity as well as a set of 63 T-cell isolates referred for clinical testing at our institution.

Methods and Materials

Probe Design—

All annotated V, D, J gene segments were retrieved from the IMGT/LIGM-DB website (www.imgt.org⁹). The 100 bp of annotated 3′ V gene coding regions and up to 100 bp, when available, of annotated 5′ J gene coding regions were selected as baits. Probes with duplicate sequences were not included.

DNA Isolation—

CD3+ T cells were isolated by flow assisted cell sorting of PBMC populations separated from whole blood. Peripheral blood mononuclear cells (PBMC) were isolated from whole blood by centrifugation followed by DNA isolation with a Gentra Puregene kit (Qiagen) according to manufacturer protocol. In the case of fresh/frozen tissues, a Qiagen Allprep (Qiagen) kit was employed, according to the manufacturer's instructions. In contrast, for FFPE samples a previously optimized in-house approach was used. First, sample FFPE tissue blocks were cored with a sterilized Tissue-Tek Quick-Ray punch (Sakura) in a pre-selected area of representative tissue; alternatively, under sterile conditions, 10×10 μm DNA curls/unstained slides were obtained for each submitted block of FFPE tissue. In a fumehood, 400-1000 μL xylene was aliquot into each tube (volume increased for larger FFPE fragments), followed by vigorous vortexing for 10 sec, incubation in a 65° C. water bath for 5 min, and centrifugation at 13200 rpm for 2 min. The supernatant was then discarded and step an additional xylene treatment step was performed. Subsequently, addition of 400-1000 μL ethanol (volume adjusted for larger input tissue volumes) was performed, followed by vigorous vortexing for 10 sec, and centrifugation at 13200 rpm for 2 min. The supernatant was then discarded and the ethanol treatment step repeated. The resulting pellet was then dried using a SpeedVac (Thermo Scientific) for 5 min, after which 150 μL of QIAamp buffer ATL (Qiagen) was added, followed by 48-hour incubation at 65° C. with 50-150 μL of proteinase K (volume increased for higher input volumes). A final ethanol clean-up step was performed, as above, to produce a purified DNA product. Resuspension in TE buffer (Qiagen) was then performed.

Hybrid Capture—

Isolated genomic DNA was diluted in TE buffer to 130 uL volumes. Shearing to ˜275 bp was then performed on either a Covaris M220 Focused-ultrasonicator or E220 Focused-ultrasonicator, depending on sample throughput, with the following settings: for a sample volume of 130 μL and desired peak length of 200 bp, Peak Incident Power was set to 175 W; duty factor was set to 10%; cycles per burst was set to 200; treatment time was set to 180 s. In addition, temperature and water levels were carefully held to manufacturer's recommendations given the instrument in use.

Illumina DNA libraries were generated from 100-1000 ng of fragmented DNA using the KAPA HyperPrep Kit (Sigma) library preparation kit following manufacturer's protocol version 5.16 employing NEXTFlex sequencing library adapters (BIOO Scientific). Library fragment size distribution was determined using the Agilent TapeStation D1000 kit and quantified by fluorometry using the Invitrogen Qubit.

Hybridization with probes specifically targeting V and J loci (Supplemental Table 3) was performed under standard SeqCap (Roche) conditions with xGen blocking oligos (IDT) and human Cot-1 blocking DNA (Invitrogen). Hybridization is performed either at 65 C overnight. The target capture panel consists of 598 probes (IDT) targeting the 3′ and 5′ 100 bp of all TR V gene regions, and 95 probes targeting the 5′ 100 bp of all TR J gene regions as annotated by IMGT (four loci, 1.8 Mb, total targeted 36 kb).

Capture Analysis—

A custom Bash/Python/R pipeline was employed for analysis of paired read sequencing data generated by Illumina NextSeq 2500 instrument from the hybrid-capture products. First, 150 bp paired reads were merged using PEAR 0.9.6 with a 25 bp overlap parameter^(A18). This results in a single 275 bp sequence for each sequenced fragment. Next, specific V, J, and D genes within the fragment sequence were identified by aligning regions against a reference sequence database. Specifically, individual BLAST databases were created using all annotated V, D, J gene segments retrieved from the IMGT/LIGM-DB website (www.imgt.org^(A9)), as these full-length gene sequences were the source of probes used to design the hybrid-capture probe panel. Individual merged reads are iteratively aligned using BLASTn with an e value cut-off of 1 to the V database, J database then D database with word size of 5 for D segment queries^(A19). Trimming of identified V or J segments in the query sequence is performed prior to subsequent alignment. From reads containing V and J sequences, we identified V/J junction position and the antigen specificity determining Complementarity Determining Region 3 (CDR3) sequences. In order to identify CDR3 sequences, the V/J junction position is extracted from the previous search data for those fragments containing both a V and J search result. 80 bp of DNA sequence flanking this junction is translated to amino acid sequence in all six open reading frames and sequences lacking stop codons are searched for invariable anchor residues using regular expressions specific for each TR class as determined by sequence alignments of polyclonal hybrid-captured data from rearranged TR polypeptides annotated by IMGT⁹

Results and Discussion

The CapTCR-seq method employs hybrid capture biotinylated probe sets designed based on all unique Variable (V) gene and Joining (J) gene annotations retrieved from the IMGT database version 1.1, LIGMDB_V12⁹. These probe sets specifically target the 3′ regions of V gene coding regions and the 5′ regions of J gene coding regions that together flank the short Diversity (D) gene fragment in heavy chain encoding loci and which together form the antigen specificity conferring CDR3 (FIG. 6A). D regions (absent in alpha and gamma rearrangements) were not probed due to their short lengths, high potential junctional diversity introduced by the recombination process, and to permit a single universal probe set for both light and heavy chain loci. These biotinylated probes are hybridized with a fragmented DNA sequencing library, and probe-target hybrid duplexes are subsequently recovered by way of streptavidin-linked magnetic beads. The subsetted library is PCR amplified from the bead-purified hybrid-duplex population using a single set of adapter-specific amplification primers and the resulting library is subjected to paired read 150 bp sequencing on an Illumina NextSeq 500 instrument. A 250 bp fragment size was selected as mid-range between the maximum length of a merged fragment from 150 bp paired-end read sequencing (275 bp) and a lower limit of 182 bp based on alignments of simulated reads centered at the VJ junction with variable insert sizes that had successful V and J alignment sensitivity of >99%.

To identify V(D)J rearrangements from the pool of captured V and J sequences, we used a computational method that performed: (1) Read merging to collapse paired reads in to a single long-read sequence to enhance V(D)J and CDR3 identification, (2) progressive BLASTn-based V, J and D detection utilizing iterative end trimming and (3) CDR3 scoring using regular expression pattern matching (FIG. 6B). This BLAST-based sequence alignment approach was employed due to its tolerance for nucleotide mismatches that could arise from junctional diversity or the presence of allelic variants not present in the reference database. We acknowledge that numerous alternative V(D)J and CDR3 calling algorithms are available^(A10-16) and these may be used in addition or in lieu of our pipeline to analyze V(D)J fragments captured by our laboratory approach. A head-to-head comparison of these methods is beyond the scope of this proof-of-principle report.

We employed this method to identify V(D)J rearrangements and CDR3 sequences in PBMCs isolated from a healthy human. With a single step hybridization and capture reaction employing the probe panel targeting TCR V genes, the number of detected unique VJ rearrangements increased with increasing amount of sample genomic DNA used to generate the initial library, with 52 times more rearrangements detected with an input of 1,000 ng compared with 100 ng (1925 vs 37) (FIG. 6C). The number of unique VJ rearrangements is dependent on the number of T cells in the original sample with an approximate fourfold increase for CD3+ sorted cells over PBMCs (2475 vs 759) (Supplemental Table 1). Addition of the J probe panel to form a single-step capture using a pooled V and J panel improved recovery of unique CDR3 sequences per 1 ng of library input by 5 fold (single-step V capture mean: 1.7, single-step VJ capture mean: 8.56) (Supplemental Table 1). This modification also increased the ratio of on-target reads, effectively decreasing the amount of sequencing needed to obtain the same number of rearranged fragments (single-step V capture mean: 14.4%, single-step VJ capture mean: 42.9%). Overall, we saw a diverse representation of alleles for all four classes with 2895 alpha, 1100 beta, 59 gamma, 9 delta unique VJ rearrangements observed from 16 independent captures of independent libraries (FIG. 9A-D). This corresponded to 6257 alpha, 4950 beta, 1802 gamma, 109 delta unique CDR3 sequences. We also submitted a portion of these samples for parallel characterization by a commercial PCR-based TCR profiling service and found similar V/J gene usage and representation with no more than 2% variation (FIG. 6D-F) and correlation with an r² value of 0.94 (FIG. 9E)

To test the ability of CapTCR-seq to assess TCR clonality of samples with a range of clonal signatures, we analyzed libraries derived from CD3+ flow-sorted Tumor Infiltrating Lymphocytes (TIL) expanded cultures (oligoclonal) and lymphoblast cell lines (clonal) (FIG. 7A-B; and data not shown). As expected, the cell-lines and antigen-specific cell-sorted samples were more clonal (12-22 unique VJ rearrangements) than the TIL cultures (123-446 unique VJ rearrangements). The predominant alpha rearrangement represented 40-80% of the recovered reads in clonal samples compared to 2.5-17.5% for the latter TIL cultures. Specifically, we detected 12 unique VJ rearrangements in L2D8, a GP100 antigen-specific tumor-infiltrating lymphocyte clone. In OV7, a mixed ovarian tumor-infiltrating lymphocyte population expanded with IL-2 treatment, we found 311 unique VJ rearrangements. We profiled two populations isolated from the same tumor M36_EZM, a cell suspension of melanoma tumor with brisk CD3 infiltration harbored 123 unique VJ rearrangements, while M36_TIL2, tumor-infiltrating lymphocytes from this tumor expanded in IL-2 harbored 446 unique VJ rearrangements, reflecting a likely expansion of low prevalence T cells. STIM1 is MART1-specific cell line made from peptide stimulation of healthy donor PBMCs, FACS sorting and expansion of tetramer+ cells from which we found 195 unique VJ rearrangements. The cell lines were found to encode previously reported gene rearrangements at the TCR beta and gamma loci, and additional rearrangements not previously reported (Supplemental Table 2)^(A1)7. Targeted PCR amplification of V/J rearrangement pairs, including the most frequently observed for each sample, was performed on these samples. We observed expected product for all prevalent rearrangements with some amplification failures for low prevalence rearrangements (Sample: Observed bands/expected bands; A037: 9/11; L2D8: 4/5; EZM: 3/4; TIL2: 8/9; OV7: 5/9; STIM1: 7/9; SE14 2005: 4/4; SE14 2033: 3/4; SE14 2034: 4/4; SE14 2035: 4/4) (data not shown). We also submitted the GP100 antigen specific L2D8 sample for beta locus profiling by a PCR-based commercial service and found VJ repertoire usage to be highly congruent (FIG. 7C-E), however the commercial service identified extensive low level VJ gene usage not present in the capture data (FIG. 7D). This signal may represent low-level alternative VJ pair antigen specific clones, or sample contamination with non-antigen specific clones.

To demonstrate the potential clinical utility of our approach, we generated DNA sequencing libraries from an unselected cohort of 63 samples submitted for clinical T-cell receptor rearrangement testing and subjected these to capture, sequencing and analysis (Supplemental Table 1). Samples were found to have varying degrees of donality, with the predominant CDR3 sequence representing up to 40% of the most clonal sample (average 12.2%; median 6.3%%, range 0.8-100%, FIG. 8A-B; and data not shown). When a clonal population was defined as having the most abundant to third most abundant rearrangements observed at two or more times the level of the next most abundant rearrangement, we observed three groups of samples: 11 with clonal enrichment of both beta and gamma rearrangements, 12 with clonal enrichment of beta or gamma rearrangements, and 41 that were polyclonal for both beta and gamma. When 61 of these samples were assessed by BIOMED2 assay we observed 73% agreement for beta (44/60) and 77% for gamma (46/60), 60% of samples were in agreement for both beta and gamma clonality measures (36/60). For the beta locus, 13 samples that were scored as clonal by BIOMED2 were scored as polyclonal based on relative prevalence when assessed by hybrid capture profiling. Six had low top clone prevalence (predominant rearrangement relative proportion of 1.3%, 1.8%, 2.6%, 3.1%, 3.4%, 3.8%) with a median unique VJ rearrangement count of 185. Seven had higher top clone prevalence (predominant rearrangement relative proportion of 7.6%, 8.4%, 8.5%, 8.8%, 11.9%, 12.1%, 16.9%) with a considerably lower median unique VJ rearrangement count of 44. These 13 samples had variable diversity but no predominant rearrangement was more than twofold enriched relative to the next most common rearrangement. Conversely, three samples that were scored as polyclonal by BIOMED2 at the beta locus were scored as clonal based on relative prevalence (predominant rearrangement relative proportion of 25.9%, 18.6%, 6.5%) with a median unique VJ rearrangement count of 191. These discrepancies could be resolved with deeper sequencing of these libraries to determine whether insufficient depth was distorting the interpretation or whether these represent incorrect interpretations by the BIOMED2 protocol. Improvements in the BIOMED2 primer sets have led to reduced false positives compared to previous generations, and can be further diminished through the use of higher resolution gel separation and additional analyses^(A2), however if available, sequencing-based methods provide a more quantitative assessment and relative comparison between all rearrangements. To determine whether there was unexpected enrichment in the A037 or lymphoma data sets we compared their gene usages (data not shown). A037 and the lymphoma collection had similar VJ usage profiles with few individual unique VJ rearrangement proportion enriched in A037 of up to 1% and more enrichments amongst the lymphoma set of up to 3% as expected given the clonal enrichment of select rearrangements in T-cell lymphomas.

In summary, CapTR-Seq allows for rapid, inexpensive and high-throughput profiling of all four loci from multiple samples of diverse types from a given DNA sequencing library with fragment size of 250 bp and sequencing length of 150 bp. This method will permit intensive monitoring of TR repertoires of patients with T-cell malignancies as well as monitoring of tumor-infiltrating lymphocytes in tumors from patients undergoing immune checkpoint blockade, adoptive cell transfer and other immunotherapies.

Example 3

Adoptive Cell Transfer (ACT) of in-vitro expanded Tumour-Infiltrating Lymphocytes (TIL) has emerged as an effective treatment for numerous types of solid tumours, often resulting in a durable response and in some cases a complete remission by the patient^(B1). This intervention effectively replaces nearly the entire heterogenous T-cell repertoire of the patient with tumour antigen and patient-specific effector T cells. Effector T-cells are integral for the adaptive immune response due to their roles in cellular cytotoxicity and cytokine production, with specificity conferred by the TCR-MHC interaction^(B2). The CD8+ effector T-cell repertoire consists of alpha/beta and gamma/delta subtypes, both polyclonal and skewing in the incidence of an antigen-specific response or malignancy^(B3). In high mutation load neoplasms, the MHC molecule often presents tumour-associated neo-antigens generated as a result of mutation that lead to clonal expansion and infiltration of tumour-infiltrating lymphocytes (TILs)^(B4). These TILs are largely clonal and distinct from the circulating repertoire in multiple types of neoplasia^(B5). While these TILs are capable of driving an effective anti-tumour response in vitro, they are often exhausted within the tumour microenvironment as a result of expression of immunosuppressive cell-surface proteins by the tumour but their activities can be restored with immune checkpoint blockade therapy^(B6). The combined effect of immunotherapy intervention: immunodepletion, TIL ACT and checkpoint blockade together present an effective treatment for many patients but have a disruptive effect on the endogenous immune repertoire and therefore proper patient care would benefit from longitudinal monitoring of the T-cell repertoire during the course of disease and treatment.

During ACT immunotherapy, both the requisite immunodepletion and T-cell transfer radically disrupt the abundance and diversity of the endogenous T-cell population and therefore molecular profiling methods are required for monitoring of the patient during the course of immunotherapy^(B7). The TCR repertoire consists of cell-specific heterodimeric receptors uniquely rearranged and expressed from either the alpha/beta or gamma/delta genomic loci^(B8). The TCR has unique specificity for an antigen presented in the context of the an MHC molecule as defined by the combined interactions of the amino acid residues encoded at the V-(D)-J junction known as the complementarity determining region 3 (CDR3), and by the CDR1 and CDR2 regions in the upstream V gene fragment.

Methods and Materials

Probe Design—

All annotated V (V-panel), D, J (J panel) gene segments and V 3′-UTR (depletion panel) sequences were retrieved from the IMGT/LIGM-DB website (www.imgt.org). The 100 bp of annotated 3′ V gene coding regions, up to 100 bp, when available, of annotated 5′ J gene coding regions, and 120 bp of V 3′-UTR sequences were selected as baits. Probes with duplicate sequences were not included. The V-panel consists of 299 probes (IDT) targeting the 3′ and 5′ 100 bp of all TR V gene regions, and the J-panel consists of 95 probes targeting the 5′ 100 bp of all TR J gene regions as annotated by IMGT (four loci, 1.8 Mb, total targeted 36 kb). The depletion-panel consists of 131 probes targeting the 5′ 120 bp of 3′-UTR Immunoglobulin V regions, and 107 probes targeting the 5′ 120 bp of 3′-UTR TCR V regions.

DNA Isolation—

CD3+ T cells were isolated by flow assisted cell sorting of PBMC populations separated from whole blood. Peripheral blood mononuclear cells (PBMC) were isolated from whole blood by centrifugation followed by DNA isolation with a Gentra Puregene kit (Qiagen) according to manufacturer protocol. In the case of fresh/frozen tissues, a Qiagen Allprep kit (Qiagen) was employed to extract DNA and RNA, according to the manufacturer's instructions. The whole blood plasma fraction was then treated with red blood cell lysis buffer and circulating DNA (cfDNA) was extracted using the Qiagen Nucleic Acid kit (Qiagen) according to manufacturer protocol.

cDNA Synthesis—

mRNA was separated from isolated total RNA using the NEBNext Poly(A) mRNA Magnetic Isolation Module (NEB) according to manufacturer's instructions. To generate cDNA, first NEBNext RNA First Strand Synthesis Module (NEB) was used followed by NEBNext RNA Second Strand Synthesis Module (NEB) according to manufacturer's instructions.

Library Preparation—

Isolated genomic DNA or synthesized cDNA was diluted in TE buffer to 130 uL volumes. Shearing to ˜275 bp was then performed on either a Covaris M220 Focused-ultrasonicator or E220 Focused-ultrasonicator, depending on sample throughput, with the following settings: for a sample volume of 130 μL and desired peak length of 200 bp, Peak Incident Power was set to 175 W; duty factor was set to 10%; cycles per burst was set to 200; treatment time was set to 180 s. In addition, temperature and water levels were carefully held to manufacturer's recommendations given the instrument in use.

Illumina DNA libraries were generated from 100-1000 ng of fragmented DNA using the KAPA HyperPrep Kit (Sigma) library preparation kit following manufacturer's protocol version 5.16 employing NEXTFlex sequencing library adapters (BIOO Scientific). Library fragment size distribution was determined using the Agilent TapeStation D1000 kit and quantified by fluorometry using the Invitrogen Qubit.

Hybrid Capture—

For cDNA derived libraries, hybridization was performed with a pooled panel of probes targeting V and J loci in equimolar concentrations. For genomic DNA derived libraries, hybridization and capture was performed iteratively with probes specifically targeting V loci, 3′-UTR sequences, or J loci under standard SeqCap (Roche) conditions with xGen blocking oligos (IDT) and human Cot-1 blocking DNA (Invitrogen). Hybridization is performed at 50 C overnight. The Capture process consisting of bead incubations and washes are performed at 50 C.

For the iterative hybridization and capture process, the first J hybridization and capture is performed in completion with terminal PCR amplification with 4 steps. Following clean-up by Agencourt AMPure XP SPRI bead purification (Beckman) this product is used as input for a subsequent depletion step. For depletion, a modified and truncated SeqCap protocol is employed wherein following incubation of the hybridization mixture with M-270 streptavidin linked magnetic beads (Invitrogen), the 15 uL hybridization reaction is separated on a magnetic rack, the supernatant is recovered and diluted to 100 uL with TE buffer, followed by clean up by standard Agencourt AMPure XP SPRI bead purification (Beckman). The depletion-probe-target-beads are discarded. The purified supernatant is then used as input for a subsequent V-panel capture and hybridization as described above, but with terminal PCR amplification with 16 or amplifications steps to achieve sufficient library for sequencing.

Capture Analysis—

A custom Bash/Python/R pipeline was employed for analysis of paired read sequencing data generated by Illumina NextSeq 2500 instrument from the hybrid-capture products. First, 150 bp paired reads were merged using PEAR 0.9.6 with a 25 bp overlap parameter. This results in a single 275 bp sequence for each sequenced fragment. Next, specific V, J, and D genes within the fragment sequence were identified by aligning regions against a reference sequence database. Specifically, individual BLAST databases were created using all annotated V, D, J gene segments retrieved from the IMGT/LIGM-DB website (www.imgt.org), as these full-length gene sequences were the source of probes used to design the hybrid-capture probe panel. Individual merged reads are iteratively aligned using BLASTn with an e value cut-off of 1 to the V database, J database then D database with word size of 5 for D segment queries. Trimming of identified V or J segments in the query sequence is performed prior to subsequent alignment. From reads containing V and J sequences, we identified V/J junction position and the antigen specificity determining Complementarity Determining Region 3 (CDR3) sequences. In order to identify CDR3 sequences, the V/J junction position is extracted from the previous search data for those fragments containing both a V and J search result. 80 bp of DNA sequence flanking this junction is translated to amino acid sequence in all six open reading frames and sequences lacking stop codons are searched for invariable anchor residues using regular expressions specific for each TR class as determined by sequence alignments of polyclonal hybrid-captured data from rearranged TR polypeptides annotated by IMGT.

Results and Discussion

Methods Improvement

We experimented with alternate capture methods, using an iterative three-step hybridization and capture, first with a J panel then molecular depletion of unrearranged V-gene sequences, then subsequently with a V panel (data not shown). The depletion probes (V-gene and J-gene) are shown in Table D. These altered protocols improved recovery of unique CDR3 sequences when normalized to reads. When compared to a one-step V-panel capture, the one-step combined VJ-panel capture increased signal by 6.84×, the two-step J and V iterative capture increased signal by 12× (no significant difference was observed for J-V or V-J iterative order), and the three-step J-depletion-V iterative capture increased signal by 31.2× (FIG. 10).

We experimented with reducing hybridization and wash temperatures to improve recovery (FIG. 11). When 50 C to 65 C in 5 C increments were tested at each step of the hybridization and capture, 50 C yielded the highest signal and diversity.

We determined the best method for depletion (FIG. 12). We found that direct reuse of the hybridization mixture following bead-probe-target separation yielded reduced signal than setting up a new reaction following Agencourt XP bead purification of the supernatant. We also found that direct separation rather than separation of the hybridization following addition of wash buffer yielded increased signal.

We tested whether depletion should be preceded by a V or J capture (FIG. 13). We found that direct depletion of the library, followed by V or J capture yielded reduced signal compared to either V-Depletion-J or J-Depletion-V, both of which had increased, yet similar yields.

Input Source Material Comparisons

To determine whether we could characterize the TCR repertoire from both low and high signal samples, we performed a series of dilution curves for CD3+ genomic DNA (FIG. 14), PBMC genomic DNA (FIG. 15), and PBMC derived cDNA (FIG. 16). Less input actually yielded a higher amount of diversity when normalized for input and reads suggesting that high input libraries are being undersequenced or that probes are being saturated and leaving behind less preferable, but still on-target, targets. Additionally, we observed yields for the cDNA samples to be ˜100× that of genomic DNA reflecting enrichment of the TCR signal as a consequence of the high level of transcript expression of the rearranged TCR gene relative to other genes. In contrast, signal from genomic DNA is a related to the fraction of the complete genome of the target sequence and capture efficiency.

Since each sequenced sample represents only a snapshot of the TCR repertoire with the extent dependent on the amount of input material and the complexity of the source repertoire, we were interested in whether the method could assay complete VJ or CDR3 saturation of a patient. We looked at unique VJ pair recovery across multiple samples derived from a single patient blood draw (FIG. 17). Beta locus VJ saturation was achieved with fewer than ten runs. With sufficient input and sequencing depth, VJ saturation could be achieved in a single run. We also looked at CDR3 saturation across these same samples and were able to achieve approximately 50% beta locus saturation (FIG. 18). This level could be achieved with fewer samples by using cDNA libraries as input with deeper sequencing.

We looked at whether the genomic DNA and cDNA samples were recapitulating the same VJ combinations at the beta locus (FIG. 19). This was largely the case with only two discordant VJ pairs showing greater (<3% overall) change.

We looked at whether the genomic DNA and cDNA samples were recapitulating the same CDR3 sequences (FIG. 20). For the most prevalent 1000 CDR3 sequences detected from genomic DNA, their correlation with cDNA prevalences had an r squared value of 0.67. Many had similar prevalences however a large number had very low or zero prevalence values in cDNA. This is likely explained by the second group consisting of non-productive rearrangements that are encoded on the alternate chromosome and which are not expressed.

Investigation of Samples from Adoptive Cell Transfer Immunotherapy

We next applied the CapTCR-Seq methodology to samples derived from expanded Tumor Infiltrating Lymphocyte (TIL) infusion populations and PBMCs from serial blood draws from patients undergoing adoptive cell transfer immunotherapy. We wanted to track clones from the TIL culture over time to determine whether they successfully colonized the patient and the extent of their population over time (FIG. 21). Repertoire profiling reveals a polyclonal and diverse baseline repertoire before treatment, a less complex oligoclonal TIL derived culture, less complex oligoclonal repertoires following chemodepletion and transfusion of the TIL infusion, and finally restoration of a more complex polyclonal repertoire over time. When compared to the baseline, highly prevalent clones in the TIL infusion product persist over time albeit in decreasing amounts. The dominant rearrangements decrease in prevalence over time as the native repertoire is reestablished however the TIL product rearrangements persist. We can observe this persistence by graphing the individual profiles for these top nine rearrangements over time (FIG. 22). We can see that while they decrease over time, they remain higher than what was found in the apheresis sample after two years.

Comparison Between Uncaptured and Captured Tumor Samples

We wished to demonstrate the value of this method for interrogating existing cDNA RNA-Seq libraries (FIG. 23). To do this, Illumina cDNA sequencing libraries were generated from FFPE-derived total RNA and subjected to sequencing followed by analysis using the TCR annotation pipeline to identify unique TCR CDR3 sequences (bulk unique CDR3). Residual library then underwent CapTCR-Seq to identify unique TCR CDR3 sequences (capture unique CDR3). The CapTCR-Seq method yielded a greatly increased number of unique CDR3 sequences (mean: 466 fold, median: 353 fold). When normalized to number of total reads sequenced, we observed a 15 fold increase in signal per read sequenced (mean: 15.2, median: 14.5, n=41).

Investigation of Tumor Repertoires from Different Cancer Types

We next wanted to characterize tumor repertoires and investigate highly prevalent TIL clones in the blood repertoire before and during anti-PDL1 immunotherapy treatment. We selected five patients, each with a different tumor type: Patient A: Head and neck; Patient B: Breast; Patient C: Ovarian; Patient D: Melanoma; Patient E: Cervical. Each patient had three sample types: Tumor tissue (extracted DNA and RNA), pre-treatment blood (extracted PBMC DNA, PBMC RNA, and plasma cfDNA), on-treatment blood (extracted plasma cfDNA).

We first queried the extent of the TCR signal in the tumor samples in terms of infiltration and clonality. TCR signal is defined as the total number of counts of fragments containing both a V and J gene region (non-unique, reads normalized) while diversity is defined as the total number of unique CDR3 sequences detected (unique, reads normalized). Overall, diversity increased with signal (FIG. 24). cfDNA samples had the lowest signal, genomic DNA samples had intermediate signal, while cDNA samples had the highest signal. Blood sample signal and diversity is similar for all five patients, however tumor signal and diversity varied. Two patients had ten-fold higher TCR signal and diversity in their tumors likely reflecting increased infiltration of immune cells (FIG. 25).

Next we assessed the clonality of the tumor sample TIL repertoire. Tumors with clonal infiltration have a larger than expected population of one or more VJ rearrangements, the population of which are significantly greater than the next most prevalent clone. Patient A appears to have a large alpha rearrangement population in its tumor compared to baseline blood, while the most prevalent beta rearrangement is only slightly enriched (FIG. 26-27). The tumor sample for patient B showed both greatly enriched top alpha and beta VJ rearrangements compared to baseline blood (data not shown). The tumor sample for patient C showed both greatly enriched top alpha and beta VJ rearrangements compared to baseline blood (data not shown). The tumor sample for patient D showed both greatly enriched top alpha (2) and beta VJ (1) rearrangements compared to baseline blood (data not shown). The tumor sample for patient E showed only a slightly enriched top beta VJ rearrangement compared to baseline blood (data not shown).

Next we assessed how the most prevalent tumor VJ rearrangements differed in terms of prevalence across the other patient samples (FIG. 28 and data not shown). In general, prevalent TIL clones were not prevalent in the blood repertoire demonstrating clonal expansion within the tumor or selective infiltration. However, for a number of the most prevalent TIL clones, we saw very high levels within the plasma samples suggesting that while these clones are actively undergoing cell death. In combination with their high tumor infiltration, this suggests that these are anti-tumor T-cells undergoing active expansion, anti-tumor cytotoxicity and turnover.

Example 4

We performed similar experiments relating to B-cells. Our design targets more than 500 V-regions and 50 J-regions within the IGH, IGK and IGL loci annotated in the IMmunoGeneTics database. This accounts for all known Ig alleles while maximizing depth of coverage in selected regions. A blast-based informatics pipeline calls V(D)J recombinations and an algorithm combining information from large-insert and soft-clipped reads are used to predict candidate rearrangements which are manually verified in Integrated Genome Viewer.

Candidate V(D)J rearrangements and translocations detected through this approach have been validated in three well-characterized cell-lines with publically available whole genome data; an additional 67 MM cell lines have been annotated for V(D)J rearrangements and translocations into IGH, IGL and IGK genes. The limit of detection was established with a cell-line dilution series. We were also able to translate these techniques to cell-free DNA. These methods are applicable to the detection of MRD in mature B-cell malignancies and immunoglobulin repertoire profiling in a many clinical scenarios including cellular immunotherapy and therapeutics with immunomodulatory effects. V(D)J and complex rearrangement annotations in 70 MM cell-lines are highly relevant in further in-vitro studies.

The B-cell V-gene and J-gene capture probes used are shown in Tables B1 and B2 respectively.

Although preferred embodiments of the invention have been described herein, it will be understood by those skilled in the art that variations may be made thereto without departing from the spirit of the invention or the scope of the appended claims. All documents disclosed herein, including those in the following reference list, are incorporated by reference.

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List of Abbreviations ATCC American Type Culture Collection (Biorepository) AUC Area-under-the-curve bp basepair BWA Burrows-Wheeler Alignment algorithm CIHI Canadian Institutes for Health Information D T-cell receptor “diversity” type gene DAD Discharge Abstracts Database (CIHI database) DSMZ Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (German Collection of Microorganisms and Cell Cultures) FDR False-Discovery Rare FFPE Formalin-fixed paraffin-embedded ICD-10 International classification of disease, version 10 IG Immunoglobulin IMGT The International standard source for ImMunoGeneTics sequences & metadata J T-cell receptor gene “join” type gene kb kilobase LGL Large-Granular-Lymphocyte (Leukemia/Lymphoma) NGS Next-generation sequencing (technology) NMF Non-negative Matrix Factorization NTRA Novel NGS-based T-cell receptor gene re-arrangement assay PEAR Paired-end rEAd mergeR PTCL Peripheral T-cell lymphoma ROC Receiver-Operating Characteristic (Curve) SAM Sequence Alignment Map SEER Surveillance, epidemiology, and end results program (the primary US source of Cancer Statistics) SWA Smith-Waterman Alignment (algorithm) TGH Toronto General Hospital TLPD T-cell lymphoproliferative disorder TR T-cell receptor TRA T-cell receptor alpha gene TRB T-cell receptor beta gene TRD T-cell receptor delta gene TRG T-cell receptor gamma gene TRGR T-cell receptor gene re-arrangement V T-cell receptor “variable” type gene WHO World Health Organization

TABLE D SEQ ID NO Name Sequence SEQ ID NO: 1 IGKV1/OR2-3*01 cccagtgcgacaagtcataacatcaaccgctaggatagcagatgagtgaggccgggttgcccta gatgctcctcctggtgcctcaatctgctgagttgttttccagatgcagccaagttt SEQ ID NO: 2 IGKV1-22*01 cctagagtgttacaggtcataaaataaacccccagggaagcagaagtatgactcatggctgccc caggtgcttccactggtgcctccatctgctgagagtgtttctcaggtgcagccaag SEQ ID NO: 3 IGKV1-27*01 cactgtgatacaagcccgaacataaaccatggagggaagtagatgtgtgaggctgggctgcccc agctgctcctcctggtgccgccctctgctgacagcagttctcagatgcagccaagg SEQ ID NO: 4 IGKV1D-37*01 cacagtgttacaaggcataacataaaccccccaaggaagcagatgtatggggctggcctgcccc agatactcctcctactgcctccagctgctcagagcgtttctcatattccagtcaag SEQ ID NO: 5 IGKV1-39*01 cacagtgttacaagtcataacataaacctccaaggaagcagatgtgtgaggacgagccacccca gatgctcctcctggtgcctccatctgctgagagcatttctcaaactcagtcaggtt SEQ ID NO: 6 IGKV1-35*01 cacagtgttacaaaccataacaaaccccccccaggaaagcagacatgtgacgctgggctgcccc acctgctcttctttgtgcagccatctggtgacaacacttctcagactcagcctgag SEQ ID NO: 7 IGKV1-32*01 cacagtgttacaaacccaataagctccccaaggaagcagatatgtgagggtgggctgccccagc tgcttctcctgtttcctccatctgctgagagtgtttctcagactcagccacactct SEQ ID NO: 8 IGHV7-81*01 caccatgtggaaacccacatcctgagagtgtcagaaatcctgatgtgggaggcagctgtgctga gctgaggcagtgatgcagcagtttccttaacttccatcttatctcattttgcatcg SEQ ID NO: 9 IGHV1-14*01 cacagtgtgaaaacccacatcctgagagagtcagaaatcctgagggaggtggcagcagtgctag gcttgagagatgacagggattttatttgctttaaaggctttttttagaaagcgagg SEQ ID NO: 10 IGHV1-69*01 gacacagtgtgaaaacccacatcctgagagtgtcagaaaccctgagggagaaggcagctgtgcc gggctgaggagatgacagggtttattaggtttaaggctgtttacaaaatgggttat SEQ ID NO: 11 IGHV1-67*01 cacagtgtgaaaactcatatcctgagagtgtcagtaaccctgagggaggaagcagctgtcccag ttttcaggatatgacaggatttatggggtttaatgttgtttagaaaataggttata SEQ ID NO: 12 IGHV1/OR21-1*01 cacaatgtgaaaacccacatcttgagagtttcagaaactgcagggaggaggcagctgtgttcct gcagaggagatgacagggaagatgaggtttaaagttgtttagaaaatgggtcaagt SEQ ID NO: 13 IGHV1/OR15-3*03 gacacagagtgaaaacccacatcctgagagtgtcagaaaccccaaggaggagcagctgtactgg agctgaggaaatggacaaagattattcagattgaagactttctacgaaaatgactt SEQ ID NO: 14 IGHV1-3*02 cacagtgtgaaaacccacatcctgagagtgtcagaaaccccaggggggaagcagctgtgctggc atggaggaaatgacaaagattattagattgaagactttctcagaaaatgatattaa SEQ ID NO: 15 IGHV1-17*01 gacacagtgcgaaaacccacatcctgagagtgtcagaaaccccaggaaggaggcacctgtgctg acacagagggagatgacaaagattattagattaacgattttcttaga SEQ ID NO: 16 IGHV1-17*02 cacagtgcgaaaacccacatcctgagagtgtcagaaaccccaggaaggaggcacctgtgctgac acagaggagatgacaaagattattagattaaagattttcttagaaaatgacactaa SEQ ID NO: 17 IGHV1-38-4*01 cacagtgtgaaaacccacatcctgagagtgtcagaaagcctgaggaaggaggcagctgtgctgg ggctgaggagatgacagggattacttgattgaagactttcttagaaaacgaggtta SEQ ID NO: 18 IGHV5-51*01 cacagtgagagaaaccagccccgagcccgtctaaaaccctccacaccgcaggtgcagaatgagc tgctagagactcactccccaggggcctctctattcatctggggaggaaacactggc SEQ ID NO: 19 IGHV5-784*01 gaccatctaaaaccttccgcggtgcaggtgcagagtgagctgccagacacaccctccccagggg cctctctattcatccggggaggaaacactggctgtttgtgtcctcaggagcaaaaa SEQ ID NO: 20 IGHV3-50*01 gcgaataatggagaacttgagatatggagtgtgagtggatatgagtgaaaaaacagtgattctg tgtggcaggttctgactcagatgtctctgtgcttgtaggtgtctagtgtggggtgc SEQ ID NO: 21 IGHV(III)-76- cacaggagatatccgtgtggcaacctaacacaggggacacctgtatttgtgtctgagcccagac 1*01 acaaacctccctgcagggagacaggaggggaccgtgtgacagacactgctcagaac SEQ ID NO: 22 IGHV3-30-22*01 ccaagtgagagctgaggacatggctgtgcatggctgtacataaggtcccaagtgagcaaacatc ggtgtgagtccagacacaacacttcctgcaaaaacaagaaaggagtctgggccgaa SEQ ID NO: 23 IGHV(III)-22-2 acaagagtcagaaaagtgtgcaggaggccgggtgaggctgtagacactgtcagcccactatgcc aatcccaccacgagtgctggagaaggtgggagtctgatgaagcttactaacaaacc SEQ ID NO: 24 IGHV(II)-44- gccgagattgcgccactgcactcagcctgggcgacagagcgagacttcgtctcaaaaaaacaaa 1D*01 aaaaaaaatcaatcattggaatactgttgttcattacaattaatgaacgtttgata SEQ ID NO: 25 IGLV(IV)-64*01 cacaggtggggaagtgggacaaaatctcagcctgctcagagtcttgttctctgatgaaatttag atcttaaaataacttatatcacttgtgtgggatgagtgagatatcccgagctcaca SEQ ID NO: 26 IGHV(II)-23-2*01 cacagcgaggggaagccattgtgcgctcagaacactctacaaatttcctccctagtgttttacc aaaactggtatatatttcagatactgaaatatttacaa SEQ ID NO: 27 IGLV(VI)-22-1*01 agtaagaccaaaaccctcctgagattcctggcttgtgtcctgacactggggctgttgggattcc tgtctttccttcaagattgttcaaataagcaccgacaatcacttccatgtgagata SEQ ID NO: 28 IGLV(V)-58*01 aaggcaaagtgaccccagtgaatgaggaagcaggacaaaaactgttttctctgctccactatga aggctgccacgtggccctgagaaacagtgcctgttttccttactactcaagaaaga SEQ ID NO: 29 IGLV(V)-66*01 ccgtttgggtaaagcacagataaatggggaaatgaggcaaaaactgtttttctactctgctacc aaggttgaaaaatggctctcagaaccagtgtctgctgacctgcatactcaaatatg SEQ ID NO: 30 IGHV(II)-20-3*01 taaaataaaataaaatgtaaaaaatgatcaataaatgaaattactatcagttgaaactcattaa atttaaagacattttctactcaagtaactataagaacatgaatgtcaagtttcaga SEQ ID NO: 31 IGLV(IV)-59*01 cacaggcagatgagaaagtgagacgaaactcagcctactaagaatggaactatggctctttttc caattgtcaaataattttcacatacacaaactattttggaagtagctactgattca SEQ ID NO: 32 IGLV7-46*02 cacagtgacagacccatgagaggaaccaagacataaacctccctcggcccttgtgatgtggaga tcacatgatcagacatgccagatcccaagatagcctacatgtggaccagccataga SEQ ID NO: 33 IGLV8-61*01 cacagtgatttaaacctatgaggaagtgcaactaaaacctctttatatactgagaacagttcag cccttacagacaggagggaaagtgagagggtggaaatggtcaacacggtgagtgag SEQ ID NO: 34 IGLV8/OR8-1*01 tttaaacccatgaggaggtgcaactaaaacctctttacatactcagaaagattcagcccttaga agcaagagagaagttgagagggtgggaatgtcaacaccatgagctgggaacctcct SEQ ID NO: 35 IGLV(I)-56*01 ttctctgattatctggatgctctgtgactccttctgtgcatctctgggatcatcattcagactc acctgcaccctgagcagtaacatcaatgttgtttgctatgacatttactggaaaca SEQ ID NO: 36 IGKV3-31*01 cacagtgattccacaggaaaccaaacctccacaagacagctggtgttttttcctcaagccttct gtttacttatgggaagctactatggtggctgcttagttattgagagaaaacaatgg SEQ ID NO: 37 IGKV3-34*01 cacagtaattcaacatgaaacaaaaactttcacaaaaccattgattttttttttctaaaaccag cagctttatgggctgcagctatgatggctgctcagttttagcaactgtgcctctat SEQ ID NO: 38 IGKV3D-25*01 catactgattcaacatgcaacaaaaacctccaggagacctaaggtgtttatttgattataccac ctgcttcctttttagtcatctgatgtggtgctgctcagttttagcatctctgcttt SEQ ID NO: 39 IGKV3-11*01 cacagtgattccacatgaaacaaaaaccccaacaagaccatcagtgtttactagattattatac cagctgcttcctttacagacagctagtggggtggccactcagtgttagcatctcag SEQ ID NO: 40 IGHV2-70*13 cacagagacacagcccagggcgcttcctgtacaagaacccaggtgtttttcagtggtgctccct ccccacttctgcagaacaggatagtgtggctgagatgccatttcctgcccagggcg SEQ ID NO: 41 IGHV2-70D*04 cacagagacacagcccagggcgcctcctgtacaagaacccaggctgcttctcagtggtgctccc tccccacctctgcagaacaggatagtgtggctgagatgccatttcctgccagggcc SEQ ID NO: 42 IGLV(VI)-25-1*01 agtaagaccaaaaccctcctgagattcctgacttgtgtcctgacaccaggtctgttcttccctc ccctagaataaaacatctcttaagcacaaggctgaagaaatgtggcctcctccttt SEQ ID NO: 43 IGHV(II)-22-1*01 cacagcgaggggaagccattgtgcgctcagaacactctacaaattttcctccctagtgttttac caaaactggtatatatttcagatactgaaatatttacaacctacgttattatgcta SEQ ID NO: 44 IGHV(II)-30- caaacaaaacgacacaaaaaattccaaagttgtgcaccctctaaaagcatatgtacttaattct 31*01 catttttaatttattaaacagctctaataagttcaatgttcctgccttctcagttg SEQ ID NO: 45 IGKV2D-36*01 aaaacttgaacttccatcaatgataaatattccttttgcctcaagcacatatttgaggaatttt ccattgagtagatctaccgataaggtcacatttttctgtctgttttaatctgaata SEQ ID NO: 46 IGHV1-12*02 tagttatttgagagatttttcatacaacatttattctgtaagcaaatttcagggattgttgaat gaatcatattaacaaatctgacacagaacttcctctgaatcaatctttgtaaacat SEQ ID NO: 47 IGHV(II)-44- tgcctggccgtaagttaccatgtgctttttaaaaaaatcatagcaaaggggtgtcttctggaaa 2D*01 tgacattttgaaatggtgttattagaccacccctggaagggacacagtaaccacac SEQ ID NO: 48 IGHV(II)-74-1 agtgatggtgggggtcctactagcctgtggcaaatggaagcatctcttttttatcagactgaat aatattgtagtgttttcttataccacatttacttcatccctttgtgcattaacact SEQ ID NO: 49 IGHV(II)-46-1*01 aaaatccattgctagtggtggtgggagtccatttgtcttgtggaaaatggcagcatttccttat tttataaggcataataatgctatgttgtgtacacataccacattgtctttatccat SEQ ID NO: 50 IGHV(II)-67-1*01 aaaatgcatggctagtgctgctggaaacccattcctactgtggcaaatggcagcatctctttta aaaggctaaataatattctattctgtatacataccacattgccattatcctttttg SEQ ID NO: 51 IGHV(II)-23-1*01 atagatggataaactaacctaggcctttgaaaataaacccttatctgagagtgaaaagataagc catagatttggagagtttgcttgcaaatcaaatatttggaaaaggacttttattac SEQ ID NO: 52 IGHV(II)-40-1*01 taggcactggatggaaagcacaggagtgggtcaggtgcatacgtgatgagtggaggatgaattc cagcccacttatcatgaattcagacaagcccacatgttcccacatgcactatatct SEQ ID NO: 53 IGHV(IV)-44-1*01 cactgtgactcgaatccagagtgaactcagacacaaacctgccctgcaggggttcttgggacca caaggggaaggatcaggtcaccagggtgtacttaggaaccactgaactgggtcagg SEQ ID NO: 54 IGHV(II)-28-1*02 cgcaatgaagggccttcattgtgagcctagacacaaccctccctgcaggggtgaataggagcag cagggggcattcggggcagtatgggggcttaggatgattgttaggggtcaggatga SEQ ID NO: 55 IGHV(II)-30- cattgtgagcctagacacaaccctccctgcaggggtgaataggagcagcagggggcattcgggg 41*01 cagtatgggggcttaggatgattgttaggggtcaggatgagcaggatcaaggcttc SEQ ID NO: 56 IGHV(II)-65-1*01 cacaacgaggggaagtcattgtgagcccagatacaaacctccctgcaggggagctcagaaagag caggaggcactcaggacaccagggaacactctggacacatcaaggcaggtgcaatg SEQ ID NO: 57 IGHV(II)-51-2*01 aacagaagagatgtcagtgtgatcccagacacaaacttccctggagaggggcccaggaccacca aagagcactcaggcccatgaaaacagggcccaagctggagaacgggtttcctgtca SEQ ID NO: 58 GHV(II)-15-1*01 cacagaaggggaggtcattgtgaggccagacacaaacctccctgcagggaagctcaggacacca gggggtgctcagacaccaagggctctcaggacacatcaaggcaggtgcaagagggg SEQ ID NO: 59 IGHV6-1*01 cacagtgaggggaagtcagtgtgagcccagacacaaacctccctgcagggatgctcaggacccc agaaggcacccagcactaccagcgcagggcccagaccaggagcaggtgtggagtta SEQ ID NO: 60 IGHV(II)-60-1*01 cagagtgaggggaccacggtgcgagctcacacccaaaccttcctggaggggtgcacaggacagc aggagtcccgatgatggaagggggtggtctggattccaggtcactctcaagatcat SEQ ID NO: 61 IGHV(II)-53-1*01 cacagtaaggtaaccacagtgggaactcacacccaaacctccctgtgggggtgcacaggacagc cacagttactcaggaccccaggattcctcaggacaccaaggggcactcaaggccat SEQ ID NO: 62 IGHV(II)-20-1*01 cacagtgaggggacatcagtgtgagcccagacacaaacctccctatgcgggttcacaggacagc atggggtgctgaggacagaggtgggcactcaggaaccagcagggaaacccaggggg SEQ ID NO: 63 IGHV3-41*01 agtgagaggaagtccgtgtgagcccagacacaaacctccctgcaggggcacgcggggccaccag agggtgcccaggatcccctgaagacagggacagcccaaaggcaggtgcagatggat SEQ ID NO: 64 IGHV3-52*01 cacagtgaggggaggtcagtgtgagcccagacacaaacctcctgcaggggcatctggagccaca agggggcgctcaggatacacagaggacaggggcagccccagggcaggtgcaggtgg SEQ ID NO: 65 IGHV3-73*02 cacagtgaggggaggtcagtgtgagcccggacacaaacctccctgcaggggcgcgcggggctac cagggggcgctcgggactcactgagggcgggacaggtcccaggaacaggtgcagcg SEQ ID NO: 66 IGHV3-42*03 cagtgagggggaggttaacgtaggcccatacacaaatctccctgcaggggcgcgcagggccaac tgggggcgctcgggacccactgaggatgggacaggtcccaggggcgggtgcagggg SEQ ID NO: 67 IGHV3-6*01 tacggtaaggagaagtcagtgtgagcccagacacaaacctcccttcagggtacctgggacaacc agggaaagcctgggacactgtgcactgtgctgaccccaggggcaagtgcaggtgct SEQ ID NO: 68 IGHV3/OR16-9*01 cacagagtgaggggaagtcagtgagagcccaggcacaaacctccctgaaggggtcccagaaacg actagggggcgccaggacactgtgcacggggctgtctccagggcaggtgcaggtgc SEQ ID NO: 69 IGHV(II)-44-2*01 aacagtgagaggaagtcaatgtgagtccagacataaaccttcctgctgagaacaatggaaagct tttcttctaagataaggaataagaaaagaatgcccagtcttaataattctaatcag SEQ ID NO: 70 IGHV3-25*02 cacagtgaggggaggtcagtgtgagcccagacacaaacctccctgcagggccatgcgggtggtt tcctttctcagctgcaggaggcgggcttattgttgcaggactctggagacttatta SEQ ID NO: 71 IGHV(II)-26-2*01 ctcagtgaggaggtgtccttatgagccctgacacaaacctgtcagggcacttaggacctccagg aagactcaagaccaccaaggggactcacgaccactggggaagggcaggttgcagta SEQ ID NO: 72 IGHV(III)-67- cacagcgagggacatttctgtgagtccagacagaaacctccctgcagggagacaagagaggact 3*01 ttgtgataaatggtgcttaggacaccagggggcactcaggacagcagagggtgctc SEQ ID NO: 73 IGHV(III)-47-1 cacggtgaggggacatctgtgtgagctcagacacaaacctgcctgcagggagacacaaacctcc ctgcatggtagatgcttctcagaaccaccagggggtgcacaggaaaccagaaggtg SEQ ID NO: 74 IGHV(III)-82*01 cataggagcaggaacatctgcgtgagcccagacacaaaatcctctgcagggagacaggagggaa tcgcatggtagatgctgattggaactaccatgtgtcgctcagaactaccaggaggt SEQ ID NO: 75 IGHV(III)-67- cacaggagagagattatctgcacaagcccagacacaaaaatctgcagggagacaggagggaact 4*01 gcatggtagatgctgctcagaagcaccagggggcactcaacacaagggggcgctca SEQ ID NO: 76 IGHV(III)-16- agacacaggagagggaatatctgcgtgagcccagacagaaaaatctctgcaggaagacaggagg 1*01 gagctgcatggtagatgctcctcagaaccaccagggcaccttggggacaacctggg SEQ ID NO: 77 IGHV3-57*02 cacaggagagggaatatctgtgtgagcccagacacaaaaatctctgcagagagacaggagggaa ctgcatggtagatgctcctcataaccacaaaggggcagtcaggaccatcaggagga SEQ ID NO: 78 IGHV(III)-5-1*01 cacatgaggaaaggccggtgtgagacacaaacctccaggaacacctgggctaatgagctgcagg gggcgctcaggacccactgatcagtcaaccacagaggggagtgcaaaggttaggac SEQ ID NO: 79 IGHV3-63*01 ccaagtgaggaaacatcggtgtgagtccagacacaaaatttcctgcagaaagaagaaaggattc tgggccgaaggggacactcagcactcacaaaacaggtggagccccagggcaggtac SEQ ID NO: 80 IGHV3-54*01 gtcaccaggtaagaagacatcagtgtgatcacagacacagaatttcctgaaataagggaggagt ctgggctaaaagggcactcaggacccacagaaaacagcggaagctctagggc SEQ 10 NO: 81 IGHV3-54*04 caccaggtaagaagacatcagtgtgaacacagacacagaatttcctgaaataagggaggagtct gggctaaaagggcactcaggacccacagaaaacaggggaagctctagggcaggtgc SEQ ID NO: 82 IGHV3-79*01 agaagacatcagtgtgaacacagacacagaggttcctgtaatgataagggaggaggctgggata aagggagcactcaagacccacagaaaacaggggaagctctagggcaggtgcagacg SEQ ID NO: 83 IGHV3-30-33*01 caccaggtaagaagacatcagtgtgaacacagacacagagtttcctgcaatgataagggaggag gctgggctaaaaggggcactcaggacccactgaaaacgggcagctctagggcaggt SEQ ID NO: 84 IGHV3-30-2*01 ccaggtaagaagacatcagtgtgaacacagacacagtttcctgcaatgataagggaggaggctg ggctaaaaggggcactcaggacccactgaaaacgggcagctctagggcaggtacag SEQ ID NO: 85 IGHV3-9*01 cacagtgaggggaagtcagcgagagcccagacaaaaacctcctgcaggaagacaggaggggcct gggctgcagagggcactcaagacacactgaaaacacggttaacactgggacaagtt SEQ 1D NO: 86 IGHV(III)-51- catcgtgatgggaagtccacgtgggctcagagacagactgccatgcaggacacagggggtggct 1*01 tggctgaagggggcactcagcacccacagaagacaggagcagcccagggcaggggc SEQ ID NO: 87 IGHV3-62*01 cgcagtgagaagtcagtgtgagcccagacacaaacctcctgcagggtacctgggacaatcaggg aaagcctgggacactgtatactgggctgtccccaggggcaagtccaggtgatataa SEQ ID NO: 88 IGHV3-19*01 cactgtgagaggacggaagtgtgagcccagacacaaacctcctgcaggaacgttgggggaaatc agctgcagggggcgctcaagacccactcatcagagtcaaccccagagcaggtgcac SEQ ID NO: 89 IGHV3-76*01 cacagtgaggagaagtcagtgtgagcccagtcacaaacctcctacaggaacgctgggaggaaaa tcagctacagggctcactcaaggcccactgatcagagtccactccagagggaggtt SEQ ID NO: 90 IGHV3-37*01 catggtgaggggaaatcagtatgagcccagccagaaacctccctgcaggaaccctggggtgggg ggaaatcagctgcagggggcactcaggacccactgatcagaatcaaccccagaagg SEQ ID NO: 91 IGHV3-23D*01 cacagtgaggggaagtcattgtgagcccagacacaaacctccctgcaggaacgatgggggtgaa atcagcggcagggggcgctcaggacccgctgatcagagtcatccgcagaggcaggt SEQ ID NO: 92 IGHV3-53*01 cacagtgaggggaggccattgtgcgcccagacacaaacctccctgcaggaacgctggggaaatc agcggcagggggcgctcaggagccactgatcagagtcagccccggaggcaggtgca SEQ ID NO: 93 IGHV4-39*07 cacagtgaggggaggtgagtgtgagcccagacaaaaacctccctgcagggaggctgagggcgcg gtcgcaggtgcagctcagggccagcagggggcgcgcggagctcacggaatacaagg SEQ ID NO: 94 IGHV4-55*02 tacacagtgaggggaggtgagtgtgagcccagacacaaacctccctacagataggcagaggggg cgggcacaggtgctgctcaggaccaacagggggcgcgcgaggcacagagcccgagg SEQ ID NO: 95 IGLV11-55*01 cacagtgagacagatgaggaagtcggacaaaaaccaaggttttaagcttgtcatttttactgaa ctggttaagaacttcagtggttaataaaatcacattaaatacaggattgttgttaa SEQ ID NO: 96 IGLV(IV)-53*01 cactgtgctctaggccaatgggaaaatcccctctgcttgtgctgcctgggctcccactaggccc ctgctgtttgtgacaacagccagcactggtggtgacgcttcagccatgtatgccct SEQ ID NO: 97 IGKV3D-41*01 cactgtgctacaacccaaaacaaaaattagctcagcctggcggaacagagaaactgaacaatac cccgtttttatgatccttgcaggtgcagttggggaaataatttaccaaataccatc SEQ ID NO: 98 IGKV7-3*01 cacagtgctttaggtctaaacaaaaacctccccaggcagctgctccctgaggctcaaatccctc agatgtggctttttatgcaggtccatcagcctgctgtcataggcttgtttgaacaa SEQ ID NO: 99 IGKV2-23*01 cacaatggttcagcaccaaacaaaagcctcctgcttggattgtcccagctgcccaaattagttc cttcactgaggagtagacagggtatatgctctaaatctatgtaacaggaagatgtt SEQ ID NO: 100 IGKV2-18*01 cacagtggtacaaccctgaacagaaacctcccttcttgctgtggttcagctgcccaaatgtgtt gtttatctggaaagcagacactgtctattatcttgggagagtaaagagaggaagat SEQ ID NO: 101 IGKV2-4*01 cacagtggtaaaaccctgaacacaaacctccctacttgggatggcccagccatccacaagtgtt tgcacgtggactgtctgcatggcagattctgagttggcttcacaggtagatgttag SEQ ID NO: 102  IGKV2/OR22-4*01 cacagtgctacatcctcgaacagaaacctccctgctggttgacccagctcgcgcatgggctgct tgtctgagggaacagctgagcagagtctttgagtctgcagaggagaaggctgttgg SEQ ID NO: 103 IGKV4-1*01 cacagtgcttcagcctcgaacacaaacctcctccccatacgctgggccagtaggtctttgctgc agcagctgcttcctctgcacacagcccccaacatgcatgcttcctctgtgtgttgg SEQ ID NO: 104 IGHV4-80*01 gggaggcggagggggcgggcgcaggtgccgctcaggaccagcagggggcgcgcggggcccacag agcaggaggccgggtcaggagcaggtgcagggagggcggggcttcctcatctgctc SEQ ID NO: 105 IGLV2-11*01 ctcagcctcctcactcagggcacaggtgacacctccagggaaagggtcacaggggtctctgggc tgatccttggtctcctgctcctcaggctcacctgggcccagcactgactcactaga SEQ ID NO: 106 IGLV(I)-70*01 tgcccttggcctgtcccgaggctgatcactccatacttgcctatgacaaacaaagagggtgcct gtggctgatcgtacagtttaagcaagggaggaagtgagactcagccacaggcccct SEQ ID NO: 107 IGLV(IV)-66-1*01 cactgtgctccagacttacggggaagtgagattagaacctcccctgcattctctctgccttgtg caggcaacaatacactgtctgggaccgagtgtggctcatcagtagcagctttgttg SEQ ID NO: 108 IGLV5-52*01 cacagtgctccagacccatgaggaagtaagacaaaaccctcccctctactctcctggtctagtg aaatcacccctgctggtggctctgaccaaatctagctcagggggtgacatctgttg SEQ ID NO: 109 IGLV1-62*01 tacagtgctccaggcttgcaggggagtgagacaagaacccccttcctcctttcccaggagggtg agtgcccagcagctactgcacaggcctggcctgtggcttctgcagttgctgtttcc SEQ ID NO: 110 IGLV6-57*01 cacagtgctccagacccatggggaagtgagacagaaactccccagagcatctctacctgggcca gtctcagcctgtctccaccagagagggtagctctcccatctctcctgtctaagtgc SEQ ID NO: 111 IGLV(I)-20*01 caccgtggtccaagttcatggggaattgagacccaaacctgccctgggctctcagcctctctct tgttctgaagatgcttcctcaccctgtgcaaggggcttcttgcagcactgccttga SEQ ID NO: 112 IGLV8/OR8-1*02 tccacagtgatttaaacccatgaggaggtgcaactaaaacctctttacatactcagaaagattc agcccttagaagcaagagagaagttgagagggtgggaatgtcaacaccatgagctg SEQ ID NO: 113 IGLV3-17*01 cacagtgacacagacagattggaaagtgagatctaaagaccttcactgtctgtatcaccctctt tctccagccatagcaggactgagcagggctggcccgggtcacctggatcgaagccc SEQ ID NO: 114 IGLV3-26*01 cactcatgggacagcagtgctactcacctcacaatgacacagacagattgggaagtgagatcta aagaccttcactgtctgtgtcaccctcttcctccagccatagcaggactgtggaga SEQ ID NO: 115 IGLV3-29*01 cacagtgacagaggcagacaaggaagtaagacacagaccccttccccatctgtgctgctgtcgt cctccagcccggcaacactgtggacaaagccatgagcatgcatgacccagttcacc SEQ ID NO: 116 IGLV4-60*02 cacagtgatacaggcagatgaggaagtgggacaaaatcctcaacctgctgaggctattgttcag tgacaatttttaattttaaaacattttctgtatgtaaaaaatctatctggatgcat SEQ ID NO: 117 IGLV10-54*02 cacagtgcctcaggccagtggggaagtgagataaaaactcaagagctccctcggcctcactgaa caggcctcacagagcactgtttaaactggaccacccaaaagacaagggatgcattc SEQ ID NO: 118 IGLV10-67*01 cacagcgcctcaggggaagtgagacgaaaactcaggagctcccctagcttcactcggtatgcgg gggcgtcatagagcactgtttaaactaaaccaaaaatgacaagggctggtttccac SEQ ID NO: 119 IGLV(I)-42*01 aacagtgctgcagtctgggaaagtgagatgagaacacgccaggtctcctaggagcatgaccttc caatggcaccacccacaaccaggacacgctggtcttgttttaccatttgtgtggat SEQ ID NO: 120 IGLV2-28*01 cacagtggacataagattgattctcaggctccaagtctggccagtgagcttctttgagactccc tgggatcccagcagtgacactgatcactattgctgtcccacacatcccaagtgatg SEQ ID NO: 121 IGLV(IV)-65*01 cagcactccagacccactgggaggttacaaaaacctcttctctgatctcctggcctggtgtagt cactcctgctggtggctctaataaagtctatctcactgggtgacttatattttaga SEQ ID NO: 122 IGLV(I)-63*01 cacagtgctccgggttgaagtaagtcagaccaaaacacacagtgtgcccagccatgaagctctc ccatgcaccccctactctgcagctaagtcaatgtgttctctcacttgtttgtccta SEQ ID NO: 123 IGLV(I)-68*01 ggcagtacttcaggccagtggggaagtgggagaaaaagctgctgcccatccagcaatggagctt ctctgtgcagcccccacttcttgggcaagtcagctgattaacgttgcttttcattt SEQ ID NO: 124 IGHV(II)-28-2*01 acacctggcctcttcgtttttattcatatattccttcagcagccactatgtcttcccactgatt tcttcagtttctgccttttccttttgaataaggctgttactcctgagggaagatgg SEQ ID NO: 125 IGHV(II)-44-3*01 ggcaggccaccaagtccagctaatttttgtatttttagtagacactgggtttcacaatattggt ctggctggtctcaaactcctgatctcagcctcccaaagtgctgggattaaagccgt SEQ ID NO: 126 IGHV3-36*01 attgtgtgcatcccttgtttaggtacatgcagagatgctgctttggtgtgttcaggggctcctg ttttggggacaccaattttggagtttgcagtatccttgagtccagtacgttcatgg SEQ ID NO: 127 IGHV(III)-25- atggtctcactgatatctttacttcttttatcacttttgttatgtaaatcacaatgaatagtgt 1*01 attcctcatctattatacatttgttaagtcttttttggtgtctttaaaaaaactga SEQ ID NO: 128 IGHV(III)-25- cacaatgaatagtgtattcctcatctattatacatttgttaagtcttttttggtgtctttaaaa 1*02 aaactgataactttatagtatgtaatatccttaagtcctgaaagtgttttttgatg SEQ ID NO: 129 IGHV(III)-11- cttcatctattatacacttgttaagtcttttttggcatcttttaaaaaactggtaactttatcc 1*01 tgtgtaatatccctgttaagtcctaaaagtcttttttgatgtctattttttcttaa SEQ ID NO: 130 IGHV(III)-20- tacctaaatgtgtgtgggggaagcagggggtgttattctgttgttctgtgttctctgagatgca 2*01 tggattcaccatttactctgcctccattttggggaacacagttagaaaaaatgtca SEQ ID NO: 131 IGHV(III)-44D*01 tggttttcagcagttttaataagattcacctaaatgtgtgtgtgtgtcgaggggtgttatgcta ttgttctgtgttctctgagatgcatggattcaccgtttactctgtctccatttt SEQ ID NO: 132 TRGV1*01 cacagtgattcagacactgaaaatctgcctgtggttgcttctggtacacaagatagaccagcca actctcatttcctgccctgaatttactgtattctgtacaaagagaaacacagctta SEQ ID NO: 133 TRGV4*01 cacagtgattcagatccgccctacaccacactgaaaacctgccttgtggctgcttctggtacac aagatagagctgccccctctcatttcctgccaccaaatttaccgtgtgctgaacaa SEQ ID NO: 134 TRGV9*01 cacagcagcagacagtttgagccatcccattcaataaatgtttattgagtctttgtttataatt acgaattgggaagccacagttaccaccagtgtgcttgtaaacagtttttaagataa SEQ ID NO: 135 TRGVA*01 cgcagccttgcatgctgccccagccctacacaaaaggactcttcctcccgatccaacaaggcct tgggcattttcacttactcttggtcccttgggtttccctgtggcatagaagaaaaa SEQ ID NO: 136 TRBV8-1*01 caataatggcaatgtggcagtttccatacatatgtttgtgctagcttttttattattatatagt aaacttctttgcctctttttatagttattgtcttgaaatatattttatctgatata SEQ ID NO: 137 TRBV22-1*01 cacaatggaagcacaaccattgtctctctgtgcggaaatgtgtcctcaccctacagcccccacc acatcctctagcttaattttttcatttttaatattttcttgagattttactatgtc SEQ ID NO: 138 TRAV1-1*01 cacagtgactatgaggcctccttaactgtgccaaaattcaaaagacaatcagtggagtacaggt gggcttgagaagttctagaacttcctgagtgtatctttgcttaccgtctaatttta SEQ ID NO: 139 TRAV1-2*01 cacggtgactatgaggcctctttagctgcaccaaaattcaaaaggcaaccacagcagcgagaag ctgtatttcctgagtgtatgcctgctgtgagttaagactggggactttggaaccag SEQ ID NO: 140 TRAV8-5*01 tcaggaccctgtgataattgtgttaactgcacaaattatagagcatgtgtgttcaaacaatatg aaatctgggcaccttgaaaaaagaacaggataacagcaatgttcagggaataagag SEQ ID NO: 141 TRBV21/OR9-2*01 cacagtgccgaatgttagcccttcttagaacacaaactcattatggacccagctcaggaaataa gtgtatgtcaggttggtacacactataataacagaaagccaacttgaaagacaata SEQ ID NO: 142 TRBV16*01 cacaatgttaaatattagctaatcttaggacacagactcatcacggactcagctcaggaagcag gtggtatactaggttggaaggaaataacagaaactagagctagcttaagccaaagg SEQ ID NO: 143 TRBV23-1*01 cacagcactgaaatgtcagttcctcttagcacacaaacttgtcacagacccagctcaggaagca ggtgatgtattaggctggaagggagtaacagaaaataactggagccagcttaagcc SEQ ID NO: 144 TRAV40*01 cactgtgttaaaagcacagtgggagctatacaaaaacctcaaaggctcagaggaagtatgtagt gaggctggaaaacccaggttgtagagccctgttctctctttcacagacagtcctgt SEQ ID NO: 145 TRDV3*01 cactatgatgcaggtgcccaggaagtcataacacaaactcctggggcacagctcagcagagctg cctcttagggcaggtcatgtctgggacttggcatccttctcttagccattttgggt SEQ ID NO: 146 TRAV2*01 cacagaggcagggaacccatgaagagctgaacagaaacagagatcacagcctttgcaggaggca aaacagagatgagcaataactttttcctccttaattcagtattacccaagcttttt SEQ ID NO: 147 TRAV16*01 cacagtagctggttttgcaaggaagcagaacacaaaccctttaaatacaggaaatatttctttg caaactctctgtatggccacagcagggcattctttctccagaaattaatattgagt SEQ ID NO: 148 TRAV8-7*01 gactgtgcctgggactgcaggaggagctgaacacaaacttcctgagacactgaggttttcagga actcaagggcacagcctgacctatttgtagcaaggtctctcatttgatgaaagtga SEQ ID NO: 149 TRAV8-6*01 cacagtgcctgagactgcaggagagctgaacacaaacctcctgagatgctgagactttctgtga ctcaagaactcaacctgtggagctttcaagagggtcccttttttctgtgcccgttt SEQ ID NO: 150 TRAV3*01 cacactgataggggctgcagggggagcagaacacaaactcttgagtctggtaaagcccattttc ttgaagtctttgttccttcacatgagaacggtgtgcttccaggatatgtcacttat SEQ ID NO: 151 TRAV801*01 cacagtgtctgggactgcaaagggagctgaacacaaacttcctaaggtgctagggagaataact gcctctgaaagattttggattctgtcacagtagaaaccatgatgttagtattttta SEQ ID NO: 152 TRAV18*01 cagagtgggagggactgcagcgagagcccagcacaaaccctggggaacgcaggtggggcctggg tgtgagccgctttgggagatgaatgaatatggactcttgttcgctgggaccccaaa SEQ ID NO: 153 TRAV9-1*01 cacagtgacagggactgcaggggaagctgagcacaaactctgagcagcacgaggggcctggctg ctgagtgtaagccactgtgatcccctctggttagggaccaggaactactctactat SEQ ID NO: 154 TRAV31*01 cactgtgaagaacatgttagaagagccttacaaaaagatcggaactcaacctgaggcaattgcc tattcccacattctcaggaaaaactcacaaaccttacccaggcatttgttagcagc SEQ ID NO: 155 TRAV38-1*01 cacaatgagatgagcagcagggagaggcttacagaaacctcagacctcagcatctgtgcaaagg tcacagggtgagagggaagtggtagggtaataggtatagaaaatcattgacttctc SEQ ID NO: 156 TRAV19*01 cacagtgagatgggtgcctgtgggagccctacaaaaacctcaacaagaggcagggctcctgggg agagactctgtcacagacaggaagaagcaaggagggtctgtgtcagcacaggtggt SEQ ID NO: 157 TRAV14/DV4*01 cacagtgacagaactgtcggagggaggtgtacaaaagccctggggacctgcttgagacctccac ctgctggagaaccaaggcgggaaatcaacatcacagacaggaagtggcta SEQ ID NO: 158 TRAV33*01 cacagaagtagaaatgacagtggaagataaacaaaaaccttagcactccataaaggaagccacc tgctcaggagcttagggaaaatacatgaagcacagacaggaagaaggcacattagt SEQ ID NO: 159 TRDV1*01 cacagtgtttgaagtgatagtaaaagcaaaacaaaaaccctagggctcaataagagaacccctc tactccccatcctttgctacaggagccaatctgaaatgcacacctgcagatctcag SEQ ID NO: 160 TRDV2*03 caccctgctgcagctctacttctgagcagctcaaaaaccactgaccaggcgcggtggctcacac ctgtaatcccagcactttgggaggccgaggtgggtggatcacgaggtcaggagatc SEQ ID NO: 161 TRBV30*01 cacactgagctgggtggggcagacatctgtgcaaaaaccccaccctctcctgagccctaaccat actccccaggggccttcacttagggactgggtggaggatatttgtaagtaggtttc SEQ ID NO: 162 TRBV20-1*01 cacagcgccaggaggggatcagacaccgcggcaagaacccctgcagctgccctccgccccagcg ggccccctgagtgctgagaggggaagcgtggagaatggaaaaccacagctttcctg SEQ ID NO: 163 TRBV29/OR9-2*01 cacagtgcagggcacagatcaaagatctaagcaagaacctcagctcccttctacccagctcccc tcacatgaacctgagggccctgtcaaggtgggacagaagaggaaaccacagctctt SEQ ID NO: 164 TRBVB*01 gccacacacactcaagatgccccagacaccctgcactccgatcttactcgttcctttactgttt tcatcctaattgccctcttacacatttgaccacacatttttggtcttggtggttgt SEQ ID NO: 165 TRGV10*02 accatactagaactgttgaaacaacatgcacaaaatcccctcccagggtctgtgcccaccacat ccttcccaacaggggcaaccacagccagtccccagctgggctcccagactcaggct SEQ ID NO: 166 TRGVB*01 cacagcatcagtgccacactgtcccacacaacaacctctgttgggtctctgcccaaccacatcc ttcccatgggagcaaactctatggactcctagctgggctcccaccctcagccttgc SEQ ID NO: 167 TRGV11*02 cacagtgttagagttgtcaagataacctacacagaaactatctccgagtctgtgcctgtccaca tccttctccatgtgggcaaccacagcggtttgctcagctgggtgcccagccggagc SEQ ID NO: 168 TRAV4*01 ctcgtgggtgacacacagtgagacagatgggcctgcacctgtgccgttttcctctgtggggtgg gagtcacagcctagaaagaagtccaaaagtgctttctaaaatttttattttcaaaa SEQ ID NO: 169 TRAV26*01 cacactgggacagatggggctgcacctgtgcaatatctccctggtggcaagtgaggaggagggt agcattcacctagagcaaaatgtcgataggagtcaaaaagtaacaagaaaagagga SEQ ID NO: 170 TRAV26-1*01 cacagtgggacagatggggctgcagctgtgcaatatctccctggtgatgaaagggaaggcatct aacgaggccactgcacaagaaggagcagaagtttaatagaggaagaagaaaattta SEQ ID NO: 171 TRBV10-1*01 cacagtgctgcacagctgcctcctctctgcacataaagggcagttagaatgactgaggttgcct gtgctcccaagtcccagccttcacaggagtcggagagccctggctagcctgggggc SEQ ID NO: 172 TRBV10-2*01 cacagtgctgcacagctgcctcctctctgcacggaaacggcagttagaaaaactgaggttgcct gtgcacccaagtctgggccccaccctgggacgtctcagcccccataggagtcacag SEQ ID NO: 173 TRBV10-3*01 cacagtgctgcatggctgcctcctctctgcacgtaaacagcagttagaaagactgaggttgctc tgtgtctatccccacccttggaagtccaggcctccatagaagtcagagggccctgg SEQ ID NO: 174 TRBV28*01 cacagcgcagcacagctgcatcctctctgcacaaaaagagcggacgtaagagagaaggggccct aactcagggctggtgctggctccgatggcacattcgtgctaaatagaaaaaaagcg SEQ ID NO: 175 TRBV6-2*01 cacagtgctgcacggctgtctcctctctgcacagaaaggcaagggaaggtgctgccctcctccg cagcacagattcagcgatgcccttggtcctagcaccgaaaactttggagccccaat SEQ ID NO: 176 TRBV6-4*01 cacagtgctgcacagccatctcctctctgtacataaatgcaggggaggctctgccctcctcccc gaccccagactcaaccatgtccttggcagagttctcagcactgggaatcttggaag SEQ ID NO: 177 TRBV609*01 cacagcgctgcaagcctgtctcctctctgcacataaaggcacagaggctctgccctcctcccac ccaagactcaaggatgccctgggcagagttctctgcaccaggaaccttggaaccca SEQ ID NO: 178 TRBV6-7*01 cacagcgctgcaaggctgtctcctctctgcacataaaggcaagggaaggtgctgccctcctccc ccacccaagactcaaggatgccctgtgcagagatctctgcaccaggaaccttggaa SEQ ID NO: 179 TRBV6-5*01 cacagcgctacaaggccgtctcctctctgcacataaaggcagggaggttctgccctcctccccc acccaagactcagggatgccctgggcagagatctctgcgccaggaaccttggaacc SEQ ID NO: 180 TRBV19*02 gccagtagtatagacacagtgaagcacggatgtcgcctctctgtgcataaatgtgcccagtcct gcttccccgaccaggtggcagggctcctctgcactctatgatggcagg SEQ ID NO: 181 TRBV19*01 cacagtgaagcacggatgtcgcctctctgtgcataaatgtgcccagtcctgcttccccgaccag gtgacagggctcctctgcactctatgatggcaggaaacgccactcagccactaagc SEQ ID NO: 182 TRBVA*01 cacagcactgcacaggcatgtgctcacctcacaaaatggcagtctcaaagggaggagtgcccac ccacaagaggctccaccctattctgagaaagaacttctttcagaggaggagagaat SEQ ID NO: 183 TRBV26/OR9-2*01 cacagcactgcatagctgccacatcctctccacataaaaaaaggtgcataccaaagaggaaaag cctgccctcaaaattcctcaccgcaaataagagaagttacctcacaggtattgaca SEQ ID NO: 184 TRBV25/OR9-2*01 cacagtgctacatagataccgacactctgcacagaaagggtcgcctctaaggtgaggacatctt gccttcagaaaccttatcttaaactacagaaacccctgcaaatcttcccagactcc SEQ ID NO: 185 TRBV27*01 cacagtgttgcacagccagctgctctctgcacaaaaacagagggtagctgcaagaacaaggaga ctcctccttcaggagacccctcaccgaccaacaggataaacttcctccatcatccc SEQ ID NO: 186 TRBV8-2*01 cgcagccctgcacagccagctgccctctgcacaaaaagggcagtcacaggctggaggtgggcac tccttatggaagcccgtgtctcaaccagaagaaaaagctgccctttctgaagctct SEQ ID NO: 187 TRBV24-1*01 cacagtgcttcttggccacctgctctctacacagaaagacagacacatgggtgagttgtttgct ctgaagggtacctggatgtgggttgtgggatgtggggtgtttagagctttcagtgg SEQ ID NO: 188 TRBV2*01 cacagccttgcaaagacaactccagcctgtgcaaaatccctcacagagctgcctccctcccagc cgccagctcccacttcctgcctaagaaaaggaagtctctggttgggtttgttcttg SEQ ID NO: 189 TRBV11-1*01 cacagcgttgcagagactttctctcctgtgcacaaaactccagggctctctccgctctactcag ctcacagcagcctttccttattcctcatcctctcagggaagaagtgagttttcaga SEQ ID NO: 190 TRBV11-2*01 cacagtgtagcagagacacttccctcctgtgcagaaaaccagaaaaccgcaggactctctcctc tctactcagctcacagcagcctttccttattcctcatcctcccaaggaagaagtga SEQ ID NO: 191 TRBV11-3*01 cacagtgtagcagagacacttccctcctgtgcagaaaaccgcaggactctctcctctctactca gctcacagcagcctttccttattcctcatcctcccaggaaagaagtgagttttcag SEQ ID NO: 192 TRBV15*01 cacagagctgcagtgcttcctgctctctgttcataaacctcattgtttcccagatccaggtgct ttctctaggacttctccctcaccacctcttacaacaataggaagtgggttggtggc SEQ ID NO: 193 TRBV12-5*01 cacagcgctgcagaatcacctgctccctgtgcagaaaccctggtgcttcctcttctcctccagt acccagcagctctcagcagcctttcttgctcctcccctagcacaggaagtacatag SEQ ID NO: 194 TRBV12-1*01 cacagcactgcagaatctccccatctctgtgcagaaaccctggtgcttcctcttctccccacag ctctcagcagtcgtcagcaaagtctttcctgctctctgctcaccatggctcacgcc SEQ ID NO: 195 TRBV7-3*01 cacagcatgacacaatcgcctccttcctgctcataaacctcctcctctctctccttgcttcctt atgatactattttgcaccaggggatcctcatctcacaccactccactgcctcttcc SEQ ID NO: 196 TRBV7-9*01 cacagcatggcacagtcgcctccttcctgctcacaaaccctcaggcacttacttctccttccag ctctcagaagccctgaacaaaggagctgccctgctctttcctcagcaaggagaatg SEQ ID NO: 197 TRBV7-2*01 cacagcatggcacagtcgcctccttcctgctcataaacctcatccttctctctccttgcagctc ctagacacccttaacagaggcttctctttgcttctccctccccatgggaaacaagt SEQ ID NO: 198 TRBV7-6*01 cacagtgtggcatagtcgcctccttcctgttcacaaacctcatccttctctctccttgcacctc ctagagacccttaacagaggcctctctttgctcctcacttttgatgggaaagaagt SEQ ID NO: 199 TRBV17*01 cacagcatggctgagtcagttccctccagggtgcaaaccctctggctgctcttctcccagttga actccaagaaaacatttgaaaaagcctcttccttatcttcctaccccagaagaaag SEQ ID NO: 200 TRBV5-7*01 cacagcccagcagagtcactgacattctgtatataaacttccgccttagctttgacttgagaac tgcaggccccacccaggtttcactccttcaagggaagcttttagttgtttggaagg SEQ ID NO: 201 TRBV5-6*01 cacagcccatcagagtcactgacgttctgtatataaacttcctgccttagctttgccttgagag ctgcaggccccacccagatttcactccttcaagggaagcttttagttgtttggaag SEQ ID NO: 202 TRBV5-1*01 cacagccctacaaagccaaccacattctgtgcacaaacctccctggcccaatgtggagcaacct cagccctgacatatctgtgagaacctggggactgcagggagaaagaaaggcaattt SEQ ID NO: 203 TRBV5-3*01 cacagccctgcagagtcactggaactctgtgcactaatctctctgcttccgtgtacagcagtct cagaccagacagctgtgagaacctggggccttcagggggaaagataaacaatttca SEQ ID NO: 204 TRBV502*01 atgcaggcctgcagagccaagaacattctgtgtacaaacatccctgccccagtgtggagaactt cagccctaacatatctgtgagaacttgaggactgtagtgggaaagaaaagcagttt SEQ ID NO: 205 TRBV4-1*01 cacagccttgcagagtcaccgctttcctgtgcagaaaccttcggggcctgccaggaagccgtgg gggccacggagggctcgggtgaacatttcctccaagagccccgaagaagcttcaga SEQ ID NO: 206 TRBV1*01 cacagccctgcagagtcaccgcctccctgtgcacaaacctcctggatctaatcagaaaaccgtg ggggcaacgcatccagctgagcctcagcactcggttcagcattctgtaagacctca SEQ ID NO: 207 TRBV3-2*02 acacagccttacagagccactgcatccctgtgcacaaacctcccggctcagccaggaagctgtg ggccgtgtgtgcacctgcacccaaggctccagtctccattccctgatggcctctga SEQ ID NO: 208 TRBV18*01 cacattgatgcagagccacatcctctcagtccacaaacatcctccagacctgccttggaaacag cggtgggccaggaagggaaacgcgttacctgtacagtgaacaggtcagctctacgg SEQ ID NO: 209 TRBV9*01 cacagccctgcatgagcatcagccttctgtgcaataacattcctgccccactcaggaagtgacg gtgaggggagggctgccagccagaggggctcaggccctggagagtggacaggcctt SEQ ID NO: 210 TRBV13*01 cacagaccctggagaattactggctttctgtacccaaaccctcctatctcacttgaggatgtaa tagggagaaggaggtgggggctgccacacaactttagccaagccccagagatgctt SEQ ID NO: 211 TRAV34*01 cacagcgatcttcaggcctctatcagctgtctccaaacctgcagctgggccacatatgctcttc tgacatggggctcctgagatgtggctgggacctttgccaagacatgaagtctcaga SEQ ID NO: 212 TRAV30*01 cacagtgatacccaggcctccaagacctgtactcaaacctaaagctgagccgcagatgctcccc tagcacagatgcccaccacaggagtatggggaacttaccagaaggttcatccatga SEQ ID NO: 213 TRAV7*01 cacagtactccctaggcacctgcaacctgtatccaaacatgcagctgggtagaagtaccataac agaagcatcagcaataggggccctgagcctgagtagacgtgaagaactaaggcatg SEQ ID NO: 214 TRAV22*01 cacagtgctccccaggcacctgcggcctgtacacaaaccctcatccgggctcggttcctctacc agtaacaaccacatcacgaggccaccgcagcagcattttgcacagcttaatattcc SEQ ID NO: 215 TRAV6*01 cacagtagtgccctggcagctgcttcctgcacccaaactctgctaactctcacaatcagagctc atggctgtgctgtctcccaaaggctaatcacagctcctgacagaatgggggggtgt SEQ ID NO: 216 TRAV27*01 cacagtgctcttgaggcacctgctgcctgcacccaaaccctgctgccagccccagtcacgaggc tgccacatgcctccagctccgcctcgcacagcttatggcatgaatagagagaacaa SEQ ID NO: 217 TRAV20*01 cacagcgttccccaggcacctgcaacttgtatcaaaaccctgcagctgaggatctgaaatgatg gcagaggtatctctgctgttcttcctcttgaaggagtatttatttaatgcccagga SEQ ID NO: 218 TRAV35/DV7*01 cacagtgctccctagtcacctgcagcctgtactcaaattctacagctgaggctctgcaactgta agatggggaacttgctacattgagcaagccctcaaaaataaactatacggaaaagc SEQ ID NO: 219 TRAV21*01 cacagtgcacaacaggcacctgcaaccaatacccaaactctatagctggggctctaactgcatg ttttatcttgagactgagcaatgtttttgcattaagaggacttctaaattgacact SEQ ID NO: 220 TRAV41*01 cacagtgctccccaggcacctggagcccgtacctaaactctaaagttgaggcatcatttcttac tcctgtctttcagacttgtctgtctctatccttggtcagatgatgtaaaatgttta SEQ ID NO: 221 TRAV37*01 cacagtgcccacagtcacctgcacccggtacctaaagcttgctgaggggcctgggcacacctcc ttttataagggccctggggcactgactataactctgctgcatacaaagggaaatat SEQ ID NO: 222 TRAV11*01 agtagtgtctccccagcacctgcagcctgtaccataacctgcagccgggacccttgacacaggc tagccttgcaggtgggagtgaagattttttttttttttttgtatagagggaacttt SEQ ID NO: 223 TRAV15*01 cacagggtccccaagcacctgcagcctgtaccacaacctgcatccgggacccttgacacagcct tgccttgcaggtgggagtgaaggtgttgtctttatatgtagagagaacttctttat SEQ ID NO: 224 TRAV17*01 cacagtgttccccaggaacctgcagcctctacgcaaaccctgccaaagcagcttcttagaagcc ctaatagtgggtagaattagtggttatgtctttcagtcaagaagagtctacaaaca SEQ ID NO: 225 TRAV10*01 cactgtgctccacaggcacttgaagccagtatgcaaacctgcacctggaggttatcaaggaggc ataggagttagagtagaccgttattttttatgcagaatatgatttcactagtgaat SEQ ID NO: 226 TRBV7-1*01 cacagcactactgctccagtgtcagcttggttccctaggaaatggggtttctagaacctgaatg ctgacaaataagagttgtatatgtgtataccatgcaacctgcgtttaaaaatgtat SEQ ID NO: 227 TRAV24*01 cacagtgctgttcaggcacctgcagcccatacgcaaacctgtgtctggtgttgcactgttacca gcattgacaaagaaccatgagtaggatggaaaagacaagttcgttgaattacagtt SEQ ID NO: 228 TRAV39*01 cacagtgctcccctgacgccaccagtctgtacccaaacctgcagctggtgggcccactcctcct gcaggaactatgactgtgaggcttcgttcactgtctgtacatttctttctgcaagg SEQ ID NO: 229 TRAV35*01 cacagtgctccccaaacacctgcagcctgtactcaaacttgcagctggaactctagtctctatg ctgccttcagctcttagtcctcttggcatgaaatgtgattatgcatgccacctttg SEQ ID NO: 230 TRAV12-2*01 cacagtgctccccagacacctgcagtctgtacccaaacctgccatgccccaggaatgcctgatg tagagcttagactgcagggtagtgaaactccccttgctctctagtttcaagtggaa SEQ ID NO: 231 TRAV29/DV5*01 cacagtgctctccaggcacctgcagcccgtactcaaacctgctttggggactcagactgggaga cacatagactcgcttccatttacacatgccaatatgagagattatgctttgaagta SEQ ID NO: 232 TRAV23/DV6*01 cacagtgctccccaggcacctgaagcctgtacccaaacctgcagttgaggttccagccaaaccc cacagtgggagcttacgtaggcagagatgtagcctagttttcatctgcatatgcaa SEQ ID NO: 233 TRAV28*01 cactgtgctcttcagacacctgcagcctatacatgaaaccatagctgaaggcctaacccatccc cgagagtggcagtaggtcccgatgtgattagcattgcattcccactgcctacatct SEQ ID NO: 234 TRAV25*01 cacagtgctccccaagcacctgctgcctgtctccaaatcttgccctgggtcttcaggagcagat catcctactctccccaaagagcgggcgccagagaaagccaaagtcacaatgtctgt SEQ ID NO: 235 TRAV32*01 cacagaactcttcaggcacctgcaacctgtactcaaacctgcaactgggagtccagtcacattc tttgtctttgaacgggttttgggttagaatggtttaccataatgtgcttgtttcta SEQ ID NO: 236 TRAV5*01 cacattgcttctcaggcacctgtatcctgtacccaaacctgcacctgggactaaagccacactc tatttcctttacctttaagtcagggattttgctgtaaggtatttttaatgtacgga SEQ ID NO: 237 TRAV13-2*01 cacattgctttccaggcatctgtaaccatcacccaaacctgagatgggaggtgaagcagcatcc ctttcctttgcaataaattttagttatagcacttgtcattttgtttgttcataagt SEQ ID NO: 238 TRAV13-1*01 gcagcaagtacacattgcttcccaggcacctgctacccgtacacaaacctgagactggagctga agctgcaccccctttcctttgtcatagatcgtcaattatagcatttgtcatattgt

TABLE B1 SEQ ID NO Name Sequence SEQ ID NO: 239 IGHV(II)-1-1*01 CACACTTCAGCCCAGCCTTTCTGGGCCAACTCTCCATCTGTAGAGACACATCCAAGGCCCA GTTATCCCTGCAGCTGAGCTCCGTGATGGCCAAGGGCAGGGCCGCACATTCCCGTGGGA SEQ ID NO: 240 IGHV(II)-20- GCTTGTTGCTCATGTAGCTCAGCCATAGGAAGAGCTGCCCCGGCGGACATAGATCTGGAGG 1*01_IGHV(II)-20- TGGCGACTGGACTCTTGAGGAGTGGGTTGGAATTTTTGCTGCCTTCATGACCTGTGCAC 1*02 SEQ ID NO: 241 IGHV(II)-22- AATCCAACCCACTCCTCAAGAGTCCAGTCACCATCTCCAGATCCACATCCAAAAAACAGTT 1*01_IGHV(II)-23- TCTCCTACAGCTGAGCTACCTTAACAAGGAGTACACAACCATGATTTTTATACAAAAGA 2*01 SEQ ID NO: 242 IGHV(II)-26-2*01 CATCATGCACCCTCCACCCAGGTCCATGTCCCCATCAACAGTGACTCAACCAAGAGCCAGT TCTCTGTGAAGCTCAGCTCCATGACCACCTAGGACACGGCTGAGTATTACTGTGAAAGA SEQ ID NO: 243 IGHV(II)-28- GTGAAGGGAGCACAAATTACAACCCACTGCTCAAGAGTCCATATCCAGATCCAAGAAACAG 1*02_IGHV(II)-28- TTCTTACAGCTGAGCTCTGTGCCCAGTGAACACACAACTACGCATTTTTAAGCAAAAGA 1*03 SEQ ID NO: 244 IGHV(II)-30- TTACTCCCCTCTTCTCAAGAGTCCAGTCACCATCTCCAGATCCATGTCCAAAAAGTAGTTC 1*01_IGHV(II)-30- TTCTTACAGCTGAACTATGTGAGGAACAAACACATAGCCATGTATTTTAGAGCAAAAGA 1*02_IGHV(II)-30- 32*01_IGHV(II)-30- 51*01 SEQ ID NO: 245 IGHV(II)-30-21*01 TTACAACCCACTTCTCAAGAGTCCATATCCGGATCCAAGAAACAGTTCTTACAGCTGAGCT CTGTGCCCAGTGAACACACAACTACGCATTTTGAAGCAAAAGATGCAATGAAGGGCCTT SEQ ID NO: 246 IGHV(II)-30-41*01 TTACAACCCACTGCTCAAGAGTCCATATCCAGATCCAAGAAACAGTTCTTACAGCTGAGCT CTGTGCCCAGTGAACACACAACTACGCATTTTTAAGCAAAAGACGCAATGAAGGGCCTT SEQ ID NO: 247 IGHV(II)-30- TTACTCCCCTCTTCTCAAGAGTCCAGTCACCATCTCCAGATCCATGTCCAAAAAGTACTTC 51*02_IGHV(II)- TTCTTACAGGTGAACTATGTGAGCAACAAACACATAGCCATGTATTTTAGAGCAAAAGA 33-1*01 SEQ ID NO: 248 IGHV(II)-31-1*01 TTACATCCCACTTCTCAAGAGTCCATATCCAGATCCAAGAAACAGTTCTTACAGCTGAGCT CTGTGCCCAGTGAACACACAACTACACATTTTGAAGCAAAAGACGCAATGAAGGGCCTT SEQ ID NO: 249 IGHV(II)-40-1*01 AGCCTGGTGAAGCCCTTGCAAACCCCCTCACTCACCTGTGCTGCCTCTGGATTCTCTGTCA CAATCAGTGCTTCCTG SEQ ID NO: 250 IGHV(II)-43-1*01 CATGAAGGGAGCACAAATTCTAACCCACTCCTCAAGAGTCCAGTCACCACCTCCAGATCTA TGTCCAAAAACAGCTCTTCGTATGGCTGAGTGACATTAGCAACAAGCACACAGCCATGT SEQ ID NO: 251 IGHV(II)-43-1D*01 CATGAAGGGAGCACAAATTCTAACCCACTCCTCAAGAGTCCAGTCACCACCTCCAGATCTA TGTCCAAAAACAGCTCTTCGTATGGCTGAGTGACATTAGCAACAAGCACACAACCATGT SEQ ID NO: 252 IGHV(II)-44-2*01 ACGATGATCCATCTCTGCAGAGCCAACTCTCCTTCTCCAGAGATTCATCCAAGAAACAATT TGACTATACCTGAGCTCTGTGACATCTGAGGACATGGTTTGTATTACTGTGCAAGACA SEQ ID NO: 253 IGHV(II)-46-1*01 GACCTGAATAGCACACACTTACCCTCTGCCTCACCTACACTGTTACTGGCCACTCCGTCAC AACCAGTCCTTACTAGTGGACCTGGATCTGCCGGCTCTCAGGGAGGGGCTGCAATGGAT SEQ ID NO: 254 IGHV(II)-49-1*01 ACGCAACCCACGCCTCAAGAGTCCAGTCACCATCTCCAGATCCACATCCAAAACACAGTTT CTTCTACAGCTGAGCTACCTGAGCAACGAGTACACAACCATGAATTTTTACACAAAAGA SEQ ID NO: 255 IGHV(II)-51-2*01 AATTCTAACCCACTCCTCATGAGCTCAGTCACCATCTCCAGATCCACGTCCAAGAACCAAA TTTTCTTTTAGCTGAGTTCTGTGACCAACAATGCCACAACCTTGTATTACTGTGAGAGG SEQ ID NO: 256 IGHV(II)-53-1*01 ATTCCAACCCACTCCTCAAGAGTCCAGTCACCATCTCCAGATCCATGTCCAAAAAGCAGTT CTTCCTACAGCCGAGCTAAGTGAGTCACAAGCACACAGCCATGTATTTTTAACAAAAGA SEQ ID NO: 257 IGHV(II)-60-1*01 AAATTCCCACCCACTCCTTATGAATCCAGTCACCATCTCCAAATTCGGGTCCAAAAAACAC TTGTTTTTACAGTGGAGCTATGTGAGCAACAAGCTCACAGCCATGTTTTAAAGAAGAGA SEQ ID NO: 258 IGHV(II)-62-1*01 ATTACTCCCCTTTCCTCAAGAGTCCAGTCACCATCCCCAGATCCATGTCCAAAAACAGTTC TTCCTACAGCTGAGCTACATGAGCAACAATCACATAGCCATATATTTTTCAGCAATAGA SEQ ID NO: 259 IGHV(II)-65-1*01 TTCCAACCCACTCCTCAAGAGTCCAGTCACTATCTCCAGATCCACATCCAAAAAACAGTGT TTCCTGTAGCTGAGCTACCTGAGCAACAAGTACACAACCATGAATTTTAATACAAAAGA SEQ ID NO: 260 IGHV(II)-67-1*01 ATGCCTAGGTGTGAAGATCACACACTGACCTCACCCATGCTGTCTCTGGCCACTTCATCAC AACCAATGCTTAATATTGGACGTGGATCTGCCAGTCCCCGGGGAATGGGTTGAATGGAT SEQ ID NO: 261 IGHV(III)-11-1*01 GGCAGCAACAGGGAGAAATTCAAGAGGAAGTTCTTACATGCACCCTTACGTGCACGGTCTC ACTGAGATCTTTACTTCCTTTATCACGTTTGTTCTGTAAATCACAACGAATGGTGCATT SEQ ID NO: 262 IGHV(III)-13-1*01 TGGGACTCTCCTTGAGTAAAAAGATGATTAACAATCCTCAAATACACTCAGTTCAGGAGAT TCTCTTTTAAGATGATTAACCTGAGAGCTCAGGAAAAGTCCGTGTATTACTTTGAGGGA SEQ ID NO: 263 IGHV(III)-16-1*01 TCAGAGTTACTCTCCATGAGTACAAATAAATTAACAGTCCCAAGCGACACCTTTTCATGTG CAGTCTACCTTAAAGGGACCAAACTGAAAGTCAAGGACAAGGCCTTGTAATACTGTGAG SEQ ID NO: 264 IGHV(III)-20-2*01 ACCAGAAGAATGCTATCATCATCTTTTCTGTTCTTTTGGAAGGAATGCCCCCTCTACTCAC CTCCACTTGCCTGCATATATTTCTATTTGTCTTTGCTTTTCAGCAGTTTTAATAAGATT SEQ ID NO: 265 IGHV(III)-2-1*01 GGGTTACTTTCCATGAGTACAAATAAATTAACAATCTCAAGCAACACCCTTTAAGTGCAGT CTGCCTTACAATGACCAATCTGAAAGCCAAGGACAAGGTCATGTATTACTGTGAGTGA SEQ ID NO: 266 IGHV(III)-25-1*01 GCAAGCTCCAGGACCAGGGTTGATGTGGGCAGCAACAGGGAGAAATTGAAGAGGAAGCTCT CAGTGGTGCCCTCCATGAATACAAAGAATCTTCACAGTCCCCAGGACACCCTTACGTGC SEQ ID NO: 267 IGHV(III)-25-1*02 AGAGGAAGCTCTCAGTGGTGCCCTCCATGAATACAAAGAATCTTCACAGTCCCCAGGACAC CCTTACGTGCATGGTCTCACTGATATCTTTACTTCCTTTATCACTTTTGTTATGTAAAT SEQ ID NO: 268 IGHV(III)-26-1*01_ GGGTTACTCTCCATGAGTACAGATAAATCAACATTCCCAAGTGACACCCTTTCAAGTGCAG IGHV(III)-26-1*02 TCTACCTTACAAGGACCAACCTGAAAGCCAAGGGCAAGGCCGTATATTACAGTGAGGGA SEQ ID NO: 269 IGHV(III)-38-1*01 AATGGGACTCGCCTTCAGTACAAAGAAGATTAACAGTCCTCAGAGACACTGTTCAGAAGAT TCTCTTTTAAGATAATAAAACTGAGAGCCCAAGACAAGTCTGTGTATTACTGTGAGGGA SEQ ID NO: 270 IGHV(III)-38-1*02 AATGGGACTCGCCTTCAGTACAAAGAAGATTAACAGTCCTCAGAGACACTGTTCAGAAGAT TCTCTTTTAAGATAATAAAACCGAGAGCCCAAGACAAGTCTGTGTATTACTGTGAGGGA SEQ ID NO: 271 IGHV(III)-38-1D*01 AGTGGGACTCTCCTTCAGTACAAAGAAGATTAACAGTCCTCAGAGACACTGTTCAGAAGAT TCTCTTTTAAGATAATTAAACCAAGAGCCCAGGACAAGTCTGTGTATTACTGTGAGGGA SEQ ID NO: 272 IGHV(III)-44*01 TTTAGGAAGAATGCCCCCTCAACTCATCTCCACTTGTCTGCATGTATTTCTATTTGTCTTG GACGTTCCCAACAGCCTCNCGAACACTCACCTCACCCTACAATGCTGCTCGAGGGGGTC SEQ ID NO: 273 IGHV(III)-44D*01 ATTTTCCTCTTGCTTATAAGGTTTTAACAGAAGAATGCTGTCATCATCTTTCCTGTTCTTT TAGAAGGAATGCCCCCTCAACTCATCTCCACTTGTCTGCATGTATTTCTATTTGTCTT SEQ ID NO: 274 IGHV(III)-5-1*01 GATTTATCATCTCAAGAGACAATGTCAAGAAGATGCTGTTTCTGCAAATGGGCAATCTGCA AACCAAGGACACGTCACTACATTACTGTGCAAGAGAAG SEQ ID NO: 275 IGHV(III)-51-1*01 CAATGCAGACTATGTTAGGGGCAGACTCACCACTTCCAGAGACAACACCAAGTACATGCTG TACATGCAAATGAACAGCCTGAGAACCCAGAACATGGCAGCATTTAACTGTGCAGGAAA

TABLE B2 SEQ ID NO Name Sequence SEQ ID NO: 276  89161040 89161073 IGKJxxx- TACACTTTTGGCCAGGGGACCAAGCTGGAAATCAGACGTAAGTACTTT Z11891 TTTCCACTGATTCTTCACTGTTGCTAATTAGTTTACTTTGTGTTCCTT TGTGTGGATTTTCATTAGTCGG SEQ ID NO: 277  89160080 89160117 IGKJ5*01- GATCACCTTCGGCCAAGGGACACGACTGGAGATTAAACGTAAGTAATT X67858 TTTCACTATTGTCTTCTGAAATTTGGGTCTGATGGCCAGTATTGACTT TTAGAGGCTTAAATAGGAGTTTGG SEQ ID NO: 278  2  89160398 89160435 IGKJ4*01- GCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGTAAGTGCAC X67858 TTTCCTAATGCTTTTTCTTATAAGGTTTTAAATTTGGAGCGTTTTTGT GTTTGAGATATTAGCTCAGGTCAA SEQ ID NO: 279  2  89160733 89160770 IGKJ3*01- ATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGTAAGTACAT X67858 CTGTCTCAATTATTCGTGAGATTTTAGTGCCATTGTATCATTTGTGCA AGTTTTGTGATATTTTGGTTGAAT SEQ ID NO: 280  2  89161037 89161075 IGKJ2*01- TGTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGTAAGTACT X67858 TTTTTCCACTGATTCTTCACTGTTGCTAATTAGTTTACTTTGTGTTCC TTTGTGTGGATTTTCATTAGTCGG SEQ ID NO: 281  2  89161398 89161435 IGKJ1*01- GTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGTGAGTAGAA X67858 TTTAAACTTTGCTTCCTCAGTTGTCTGTGTCTTCTGTTCCCTGTGTCT ATGAAGTGATCTATAAGGTGACTC SEQ ID NO: 282  2  89161398 89161433 IGKJ1*01- GGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGTGAGTAGAATT X63370 TAAACTTTGCTTCCTCAGTTGTCTGTGTCTTCTGTTCCCTGTGTCTAT GAAGTGATCTATAAGGTGACTCTG SEQ ID NO: 283  2  23235961 23235998 IGLJ1*01- GGCTCCTGCTCCAGCCCAGCCCCCAGAGAGCAGACCCCAGGTGCTGGC X51755 CCCGGGGGTTTTGGTCTGAGCCTCAGTCACTGTGTTATGTCTTCGGAA CTGGGACCAAGGTCACCGTCCTAG SEQ ID NO: 284  2  23235961 23238998 IGLJ1*01- TTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTAGGTAAGTGGCT X51755(2) CTCAACCTTTCCCAGCCTGTCTCACCCTCTGCTGTCCCTGGAAAATCT GTTTTCTCTCTCTGGGGCTTCCTC SEQ ID NO: 285 22  23241798 23241835 IGLJ2*01- CAGCTTCCTCCTTCACAGCTGCAGTGGGGGCTGGGGCTGGGGCATCCC X51755 AGGGAGGGTTTTTGTATGAGCCTGTGTCACAGTGTGTGGTATTCGGCG GAGGGACCAAGCTGACCGTCCTAG SEQ ID NO: 286 22  23241798 23241835 IGLJ2*01- TGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTGAGTCTCT X51755(2) TCTCCCCTCTCCTTCCCCACTCTTGGGACAATTTCTGCTGTTTTTGTT TGTTTCTGTATCTTGTCTCAACTT SEQ ID NO: 287 22  23241801 23241835 IGLJ3*02- CAGCTTCCTCCTTCACAGCTGCAGTGGGGGCTGGGGCTGGGGCATCCC D87023 AGGGAGGGTTTTTGTATGAGCCTGTGTCACAGTGTTGGGTGTTCGGCG GAGGGACCAAGCTGACCGTCCTAG SEQ ID NO: 288 22  23241801 23241835 IGLJ3*02- TTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTGAGTCTCT D87023(2) TCTCCCCTCTCCTTCCCCGCTCTTGGGACAATTTCTGCTGTTTTTGTT TGTTTCTGTATCTTGTCTCAACTT SEQ ID NO: 289 22  23247168 23247205 IGLJ3*02- AGCTTCCTCCTTCACAGCTGCAGTGGGGGCTGGGGCTAGGGGCATCCC D87023 AGGGAGGGTTTTTGTATGAGCCTGTGTCACAGTGTTGGGTGTTCGGCG GAGGGACCAAGCTGACCGTCCTAG SEQ ID NO: 290 22  23247168 23247205 IGLJ3*02- TTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTGAGTCTCT D87023(2) TCTCCCCTCTCCTTCCCCGCTCTTGGGACAATTTCTGCTGTTTTTGTT TGTTTCTGTATCTTGTCTCAACTT SEQ ID NO: 291 22  23247171 23247205 IGLJ3*01- AGCTTCCTCCTTCACAGCTGCAGTGGGGGCTGGGGCTAGGGGCATCCC X51755 AGGGAGGGTTTTTGTATGAGCCTGTGTCACAGTGTGTGGTATTCGGCG GAGGGACCAAGCTGACCGTCCTAG SEQ ID NO: 292 22  23247171 23247205 IGLJ3*01- TGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTGAGTCTCT X51755(2) TCTCCCCTCTCCTTCCCCGCTCTTGGGACAATTTCTGCTGTTTTTGTT TGTTTCTGTATCTTGTCTCAACTT SEQ ID NO: 293 22  23252740 23252777 IGLJ4*01- GTATTTGGTGGAGGAACCCAGCTGATCATTTTAGATGAGTCTCTTCTT X51755 CCCTTTCTTTCCCTGCCAAGTTGGTGACAATTTTATTCTGATTTCGAT CTTTGTCTGTGACTTGCCACAGCC SEQ ID NO: 294 22  23252740 23252777 IGLJ4*01- TTTTGTATTTGGTGGAGGAACCCAGCTGATCATTTTAGATGAGTCTCT X51755(2) TCTTCCCTTTCTTTCCCTGCCAAGTTGGTGACAATTTTATTCTGATTT CGATCTTTGTCTGTGACTTGCCAC SEQ ID NO: 295 22  23256443 23256480 IGLJ5*02- CAGAGAGGGTTTTTGTATGAGCCTGTGTCACAGCACTGGGTGTTTGGT D87017 GAGGGGACGGAGCTGACCGTCCTAGATGAGTCTTTTCCCCCTCCTTCC CTGGTCTCCCCAAGGTACTGGGAA SEQ ID NO: 296 22  23256443 23256480 IGLJ5*02- CTGGGTGTTTGGTGAGGGGACGGAGCTGACCGTCCTAGGATGAGTCTT D87017(2) TTCCCCCTCCTTCCCTGGTCTCCCCAAGGTACTGGGAAATTTTCTGCT GCTTTTGTTCTTTTCTGTATCTTG SEQ ID NO: 297 22  23260336 23260373 IGLJ6*01- GGAGGGTTTGTGTGCAGGGTTATATCACAGTGTAATGTGTTCGGCAGT X58181 GGCACCAAGGTGACCGTCCTCGGTGAGTCCCCTTTTCTATTCTTTTGG GTCTAGGGTGAGATCTGGGGAGAC SEQ ID NO: 298 22  23260336 23260373 IGLJ6*01- TAATGTGTTCGGCAGTGGCACCAAGGTGACCGTCCTCGGTGAGTCCCC X58181(2) TTTTCTATTCTTTTGGGTCTAGGGTGAGATCTGGGGAGACTTTTCTGT CCTTTCTGTTCTCTCTAGGGTAGA SEQ ID NO: 299 22  23263570 23263607 IGLJ7*01- TCACTGTGTGCTGTGTTCGGAGGAGGCACCCAGCTGACCGTCCTCGGT X57808 AAGTCTCCCCGCTTCTCTCCTCTTTGAGATCCCAAGTTAAACACGGGG AGTTTTTCCCTTTCCTGTCTGTCG SEQ ID NO: 300 22  23263570 23263607 IGLJ7*01- TGCTGTGTTCGGAGGAGGCACCCAGCTGACCGTCCTCGGTAAGTCTCC X57808(2) CCGCTTCTCTCCTCTTTGAGATCCCAAGTTAAACACGGGGAGTTTTTC CCTTTCCTGTCTGTCGAAGGCTAA SEQ ID NO: 301 22  23263570 23263607 IGLJ7*02- TCACTGTGTGCTGTGTTCGGAGGAGGCACCCAGCTGACCGCCCTCGGT D87017 AAGTCTCCCCGCTTCTCTCCTCTTTGAGATCCCAAGTTAAACACGGGG AGTTTTTCCCTTTCCTGTCTGTCG SEQ ID NO: 302 22  23263570 23263607 IGLJ7*02- TGCTGTGTTCGGAGGAGGCACCCAGCTGACCGCCCTCGGTAAGTCTCC D87017(2) CCGCTTCTCTCCTCTTTGAGATCCCAAGTTAAACACGGGGAGTTTTTC CCTTTCCTGTCTGTCGAAGGCTAA SEQ ID NO: 303 22 106329408 1.06E+08 IGHJ6*03- TACTACTACTACTACTACATGGACGTCTGGGGCAAAGGGACCACGGTC M63030 ACCGTCTCCTCAGGTAAGAATGGCCACTCTAGGGCCTTTGTTTTCTGC TACTGCCTGTGGGGTTTCCTGAGC SEQ ID NO: 304 22 106329408 1.06E+08 IGHJ6*03- ATTACTACTACTACTACTACATGGACGTCTGGGGCAAAGGGACCACGG M63030(2) TCACCGTCTCCTCAGGTAAGAATGGCCACTCTAGGGCCTTTGTTTTCT GCTACTGCCTGTGGGGAATTC SEQ ID NO: 305 14 106329408 1.06E+08 IGHJ6*04- ATTACTACTACTACTACGGTATGGACGTCTGGGGCAAAGGGACCACGG AJ879487 TCACCGTCTCCTCAGGTAAGAATGGCCACTCTAGGGCCTTTGTTTTCT GCTACTGCCTGTGGGGTTTCCTGA SEQ ID NO: 306 14 106329409 1.06E+08 IGHJ6*03- TGATGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTC X86359 AGGTAAGATGGCTTTCCTTCTGCCTCCTTTCTCTGGGCCCAGCGTCCT CTGTCCTGGAGCTGGGAGATAATG SEQ ID NO: 307 14 106329626 1.06E+08 IGHJ3P*02- CTTGCAGTTGGACTTCCCAGGCCGACAGTGGTCTGGCTTCTGAGGGGT X97051 CAGGCCAGAATGTGGGGTACGTGGGAGGCCAGCAGAGGGTTCCATGAG AAGGGCAGGACAGGGCCACGGACA SEQ ID NO: 308 14 106330024 1.06E+08 IGHJ4- GACTATTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGAGTCC U42590 TCACAAGCTCTCTCCTACTTTAACTCAGAAGACTCTCACTGCATTTTT GGGGGGAGATAAGGGTGCTGGGTC SEQ ID NO: 309 14 106330024 1.06E+08 IGHJ4*02- ACTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAG X97051 GTGAGTCCTCACAACCTCTCTCCTGCTTTAACTCTGAAGGGTTTTGCT GCATTTTTGGGGGGAAATAAGGGT SEQ ID NO: 310 14 106330024 1.06E+08 IGHJ4- AACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA U42588 GGTGAGTCCTCACCACCCCCTCTCTGAGTCCACTTAGGGAGACTCAGC TTGCCAGGGTCTCAGGGTCAGAGT SEQ ID NO: 311 14 106330024 1.06E+08 IGHJ5- CAGTGCTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA M18810 GGAGATTCCTCACCACCCCCTCTCTGAGTCCTCTTAGTGAGACTCAGT TTGCCGGACTCTCAGGGTCAGAGT SEQ ID NO: 312 14 106330024 1.06E+08 IGHJ5*02- ACAACTGGTTCGACCCCTGGGGCCAGGGAACCCTGGTCACCGTCTCCT X97051 CAGGTGAGTCCTCACCACCCCCTCTCTGAGTCCACTTAGGGAGACTCA GCTTGCCAGGGTCTCAGGGTCAGA SEQ ID NO: 313 14 106330425 1.06E+08 IGHJ5*02- TACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGT X97051 GAGTCCTCACAACCTCTCTCCTGCTTTAACTCTGAAGGGTTTTGCTGC ATTTCTGGGGGGAAATAAGGGTGC SEQ ID NO: 314 14 106330425 1.06E+08 IGHJ4- TTTGACTGCTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGAG U42588 CCCTCACAACCTCTCTCCTGGGTTAACTCTGAAGGGTTTTGCTGCATT TTTGGGGGGAAATAAGGGTGCTGG SEQ ID NO: 315 14 106330797 1.06E+08 IGHJ3*02- TGATGCTTTTGATGTCTGGGGCCAAGGGACAATGGTCACCGTCTCTTC X97051 AGGTAAGATGGGCTTTCCTTCTGCCTCCTTTCTCTGGCCCCAGCGTCC TCTGTCCTGGAGCTGGGAGATAAT SEQ ID NO: 316 14 106330797 1.06E+08 IGHJ3*02- TGATGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTC X97051 AGGTAAGATGGCTTTCCTTCTGCCTCCTTTCTCTGGGCCCAGCGTCCT CTGTCCTGGAGCTGGGAGATAATG SEQ ID NO: 317 14 106330797 1.06E+08 IGHJ3*02- GATGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCA X97051(2) GGTAAGATGGCTTTCCTTCTGCCTCCTTTCTCTGGGCCCAGCGTCCTC TGTCCTGGAGCTGGGAGATAATGT SEQ ID NO: 318 14 106331001 1.06E+08 IGHJ2P*01- GCTACAAGTGCTTGGAGCACTGGGGCCAGGGCAGCCCGGCCACCGTCT X97051 CCCTGGGAACGTCACCCCTCCCTGCCTGGGTCTCAGCCCGGGGGTCTG TGTGGCTGGGGACAGGGACGCCGG SEQ ID NO: 319 14 106331409 1.06E+08 IGHJ2*01- CTACTGGTACTTCGATCTCTGGGGCCGTGGCACCCTGGTCACTGTCTC X97051 CTCAGGTGAGTCCCACTGCAGCCCCCTCCCAGTCTTCTCTGTCCAGGC ACCAGGCCAGGTATCTGGGGTCTG SEQ ID NO: 320 14 106331617 1.06E+08 IGHJ1*01- GCTGAATACTTCCAGCACTGGGGCCAGGGCACCCTGGTCACCGTCTCC X97051 TCAGGTGAGTCTGCTGTCTGGGGATAGCGGGGAGCCAGGTGTACTGGG CCAGGCAAGGGCTTTGGCTTCAGA SEQ ID NO: 321 14 106331834 1.06E+08 IGHJ1P*01- AAAGGTGCTGGGGGCCCCTGGACCCGACCCGCCCTGGAGACCGCAGCC X97051 ACATCAAGCCCCCAGCCCCACAGGCCCCCTACCAGCCGCAGGGTTTTG GCTGAGCTGAGAACCACTGTGCTA

TABLE 2.1 SEQ ID NO Name Sequence SEQ ID NO: 322 TRAV1-1*01-5′ ggacaaagccttgagcagccctctgaagtgacagctgtggaaggagccattgtccagata aactgcacgtaccagacatctgggttttatgggctgtcct SEQ ID NO: 323 TRAV1-1*01-3′ gtttttcttcattccttagtcgctctgatagttatggttacctccttctacaggagctcc agatgaaagactctgcctcttacttctgcgctgtgagaga SEQ ID NO: 324 TRAV1-1*02-5′ ggacaaagccttgagcagccctctgaagtgacagctgtggaaggagccattgtccagata aactgcacgtaccagacatctgggttttatgggctgtcct SEQ ID NO: 325 TRAV1-1*02-3′ caggtcgtttttcttcattccttagtcgctctgatagttatggttacctccttctacagg agctccagatgaaagactctgcctcttacttctgcgctgt SEQ ID NO: 326 TRAV1-1*01-5′ ggacaaaacattgaccagcccactgagatgacagctacggaaggtgccattgtccagatc aactgcacgtaccagacatctgggttcaacgggctgttct SEQ ID NO: 327 TRAV1-1*01-3′ gtttttcttcattccttagtcggtctaaagggtacagttacctccttttgaaggagctcc agatgaaagactctgcctcttacctctgtgctgtgagaga SEQ ID NO: 328 TRAV1-1*02-5′ ggacaaaaacattgaccagcccactgagatgacagctacggaaggtgccattgtccagat caactgcacgtaccagacatctgggttcaacgggctgttct SEQ ID NO: 329 TRAV1-1*02-3′ catctgggttcaacgggctgttctggtaccagcaacatgctggcgaagcacccacatttc tgtcttacaatgttctggatggtctggaggagaaaggtcg SEQ ID NO: 330 TRAV10*01-5′ aaaaaccaagtggagcagagtcctcagtccctgatcatcctggagggaaagaactgcact cttcaatgcaattatacagtgagccccttcagcaacttaa SEQ ID NO: 331 TRAV10*01-3′ agatatacagcaactctggatgcagacacaaagcaaagctctctgcacatcagagcctcc cagctcagcgattcagcctcctacatctgtgtggtgagcg SEQ ID NO: 332 TRAV11*01-5′ ctacatacactggagcagagtccttcattcctgaatattcaggagggaatgcatgccgtt cttaattgtacttatcaggagagaacactcttcaatttcc SEQ ID NO: 333 TRAV11*01-3′ caaatattttaaagaactgcttggaaaagaaaaattttatagtgtttggaatatcgcagc ctctcatctgggagattcagccacctacttctgtgctttg SEQ ID NO: 334 TRAV12-1*01-5′ cggaaggaggtggagcaggatcctggacccttcaatgttccagagggagccactgtcgct ttcaactgtacttacagcaacagtgcttctcagtctttct SEQ ID NO: 335 TRAV12-1*01-3′ aggtttacagcacagctcaatagagccagccagtatatttccctgctcatcagagactcc aagctcagtgattcagccacctacctctgtgtggtgaaca SEQ ID NO: 336 TRAV12-1*02-5′ cggaaggaggtggagcaggatcctggacccttcaatgttccagagggagccactgtcgct ttcaactgtacttacagcaacagtgcttctcagtctttct SEQ ID NO: 337 TRAV12-1*02-3′ acagcacacgtcaatagagccagccagtatatttccctgctcatcagagactccaagctc agtgattcagccacctacctctgtgtggtgaacattcgcc SEQ ID NO: 338 TRAV12-2*01-5′ cagaaggaggtggagcagaattctggacccctcagtgttccagagggagccattgcctct ctcaactgcacttacagtgaccgaggttcccagtccttct SEQ ID NO: 339 TRAV12-2*01-3′ aggtttacagcacagctcaataaagccagccagtatgtttctctgctcatcagagactcc cagcccagtgattcagccacctacctctgtgccgtgaaca SEQ ID NO: 340 TRAV12-2*02-5′ cagaaggaggtggagcagaattctggacccctcagtgttccagagggagccattgcctct ctcaactgcacttacagtgaccgaggttcccagtccttct SEQ ID NO: 341 TRAV12-2*02-3′ gtttacagcacagctcaataaagccagccagtatgtttctctgctcatcagagactccca gcccagtgattcagccacctacctctgtgccgtgtaccac SEQ ID NO: 342 TRAV12-2*03-5′ ggacccctcagtgttccagagggagccattgcctctctcaactgcacttacagtgaccga gtttcccagtccttcttctggtacagacaatattctggga SEQ ID NO: 343 TRAV12-2*03-3′ aaggtttacagcacagctcaataaagccagccagtatgtttctctgctcatcagagactc ccagcccagtgattcagccacctacctctgtgccgtgaac SEQ ID NO: 344 TRAV12-3*01-5′ cagaaggaggtggagcaggatcctggaccactcagtgttccagagggagccattgtttct ctcaactgcacttacagcaacagtgcttttcaatacttca SEQ ID NO: 345 TRAV12-3*01-3′ aggtttacagcacaggtcgataaatccagcaagtatatctccttgttcatcagagactca cagcccagtgattcagccacctacctctgtgcaatgagcg SEQ ID NO: 346 TRAV12-3*02-5′ cagaaggaggtggagcaggatcctggaccactcagtgttccagagggagccattgtttct ctcaactgcacttacagcaacagtgcttttcaatacttca SEQ ID NO: 347 TRAV12-3*02-3′ aggtttacagcacaggtcgataaatccagcaagtatatctccttgttcatcagagactca cagcccagtgattcagccacctacctctgtgcaatgagcg SEQ ID NO: 348 TRAV13-1*01-5′ ggagagaatgtggagcagcatccttcaaccctgagtgtccaggagggagacagcgctgtt atcaagtgtacttattcagacagtgcctcaaactacttcc SEQ ID NO: 349 TRAV13-1*01-3′ cgaattgctgttacattgaacaagacagccaaacatttctccctgcacatcagagagacc caacctgaagactcggctgtctacttctgtgcagcaagta SEQ ID NO: 350 TRAV13-1*02-5′ ggagagaatgtggagcagcatccttcaaccctgagtgtccaggagggagacagcgctgtt atcaagtgtacttattcagacagtgcctcaaactacttcc SEQ ID NO: 351 TRAV13-1*02-3′ tgttacattgaacaagacagccaaacatttctccctgcacatcacagagacccaacctga agactcggctgtctacttctgtgcagcaagtaggaaggac SEQ ID NO: 352 TRAV13-1*03-5′ ggagagaatgtggagcagcatccttcaaccctgagtgtccaggagggagacagcgctgtt atcaagtgtacttattcagacagtgcctcaaactacttcc SEQ ID NO: 353 TRAV13-1*03-3′ gcttattatagacattcgttcaaatgtgggcgaaaagaaagaccaacgaattgctgttac attgaacaagacagccaaacatttctccctgcagatcaca SEQ ID NO: 354 TRAV13-2*01-5′ ggagagagtgtggggctgcatcttcctaccctgagtgtccaggagggtgacaactctatt atcaactgtgcttattcaaacagcgcctcagactacttca SEQ ID NO: 355 TRAV13-2*01-3′ agagtcaccgttttattgaataagacagtgaaacatctctctctgcaaattgcagctact caacctggagactcagctgtctacttttgtgcagagagaata SEQ ID NO: 356 TRAV13-2*02-5′ ggagagagtgtggggctgcatcttcctaccctgagtgtccaggagggtgacaactctatt atcaactgtgcttattcaaacagcgcctcagactacttca SEQ ID NO: 357 TRAV13-2*02-3′ caaagagtcaccgttttattgaataagacagtgaaacatctctctctgcaaattgcagct actcaacctggagactcagctgtctacttttgtgcagaga SEQ ID NO: 358 TRAV14/DV4*01-5′ gcccagaagataactcaaacccaaccaggaatgttcgtgcaggaaaaggaggctgtgact ctggactgcacatatgacaccagtgatccaagttatggtc SEQ ID NO: 359 TRAV14/DV4*01-3′ actcattgaatttccagaaggcaagaaaatccgccaaccttgtcatctccgcttcacaac tgggggactcagcaatgtacttctgtgcaatgagagaggg SEQ ID NO: 360 TRAV14/DV4*02-5′ gcccagaagataactcaaacccaaccaggaatgttcgtgcaggaaaaggaggctgtgact ctggactgcacatatgacaccagtgatcaaagttatggtc SEQ ID NO: 361 TRAV14/DV4*02-3′ actcattgaatttccagaaggcaagaaaatccgccaaccttgtcatctccgcttcacaac tgggggactcagcaatgtatttctgtgcaatgagagaggg SEQ ID NO: 362 TRAV14/DV4*03-5′ gcccagaagataactcaaacccaaccaggaatgttcgtgcaggaaaaggaggctgtgact ctggactgcacatatgacaccagtgatccaagttatggtc SEQ ID NO: 363 TRAV14/DV4*03-3′ aggtcgctactcattgaatttccagaaggcaagaaaatccgccaaccttgtcatctccgc ttcacaactgggggactcagcaatgtatttctgtgcaatg SEQ ID NO: 364 TRAV14/DV4*04-5′ cagaagataactcaaacccaaccaggaatgttcgtgcaggaaaaggaggctgtgactctg gactgcacatatgacaccagtgatcaaagttatggtctct SEQ ID NO: 365 TRAV14/DV4*04-3′ gcaacagaaggtcgctactcattgaatttccagaaggcaagaaaatccgccaaccttgtc atctccgcttcacaactgggggactcagcaatgtacttct SEQ ID NO: 366 TRAV15*01-5′ ctccatattctggagtagagtccttcattcattcctgagtatccgggagggaatgcacaa cattcttaattgcacttatgaggagagaacgttctcttaa SEQ ID NO: 367 TRAV15*01-3′ acattttaaagaagcgcttggaaaagagaagttttatagtgttttgaatatgctggtctc tcatcctggagattcaggcacctacttctgtgctttgagg SEQ ID NO: 368 TRAV16*01-5′ gcccagagagtgactcagcccgagaagctcctctctgtctttaaaggggccccagtggag ctgaagtgcaactattcctattctgggagtcctgaactct SEQ ID NO: 369 TRAV16*01-3′ gcttcactgctgaccttaacaaaggcgagacatctttccacctgaagaaaccatttgctc aagaggaagactcagccatgtattactgtgctctaagtgg SEQ ID NO: 370 TRAV17*01-5′ agtcaacagggagaagaggatcctcaggccttgagcatccaggagggtgaaaatgccacc atgaactgcagttacaaaactagtataaacaatttacagt SEQ ID NO: 371 TRAV17*01-3′ agattaagagtcacgcttgacacttccaagaaaagcagttccttgttgatcacggcttcc cgggcagcagacactgcttcttacttctgtgctacggacg SEQ ID NO: 372 TRAV18*01-5′ ggagactcggttacccagacagaaggcccagttaccctccctgagagggcagctctgaca ttaaactgcacttatcagtccagctattcaacttttctat SEQ ID NO: 373 TRAV18*01-3′ gttttcaggccagtcctatcaagagtgacagttccttccacctggagaagccctcggtgc agctgtcggactctgccgtgtactactgcgctctgagaga SEQ ID NO: 374 TRAV19*01-5′ gctcagaaggtaactcaagcgcagactgaaatttctgtggtggagaaggaggatgtgacc ttggactgtgtgtatgaaacccgtgatactacttattact SEQ ID NO: 375 TRAV19*01-3′ attcttggaacttccagaaatccaccagttccttcaacttcaccatcacagcctcacaag tcgtggactcagcagtatacttctgtgctctgagtgaggc SEQ ID NO: 376 TRAV2*01-5′ aaggaccaagtgtttcagccttccacagtggcatcttcagagggagctgtggtggaaatc ttctgtaatcactctgtgtccaatgcttacaacttcttct SEQ ID NO: 377 TRAV2*01-3′ agggacgatacaacatgacctatgaacggttctcttcatcgctgctcatcctccaggtgc gggaggcagatgctgctgtttactactgtgctgtggagga SEQ ID NO: 378 TRAV2*02-5′ aaggaccaagtgtttcagccttccacagtggcatcttcagagggagctgtggtggaaatc ttctgtaatcactctgtgtccaatgcttacaacttcttct SEQ ID NO: 379 TRAV2*02-3′ gggacgatacaacatgacctatgaacggttctcttcatcgctgctcatcctccaggtgcg ggaggcagatgctgctgtttactactgtgctgtggcctgg SEQ ID NO: 380 TRAV20*01-5′ gaagaccaggtgacgcagagtcccgaggccctgagactccaggagggagagagtagcagt cttaactgcagttacacagtcagcggtttaagagggctgt SEQ ID NO: 381 TRAV20*01-3′ aaagaaaggctaaaagccacattaacaaagaaggaaagctttctgcacatcacagcccct aaacctgaagactcagccacttatctctgtgctgtgcagg SEQ ID NO: 382 TRAV20*02-5′ gaagaccaggtgacgcagagtcccgaggccctgagactccaggagggagagagtagcagt ctcaactgcagttacacagtcagcggtttaagagggctgt SEQ ID NO: 383 TRAV20*02-3′ aaaggagaaagaaaggctaaaagccacattaacaaagaaggaaagctttctgcacatcac agcccctaaacctgaagactcagccacttatctctgtgct SEQ ID NO: 384 TRAV20*03-5′ gaagaccaggtgacgcagagtcccgaggccctgagactccaggagggagagagtcgcagt ctcaactgcagttacacagtcagcggtttaagagggctgt SEQ ID NO: 385 TRAV20*03-3′ agaaaaggagaaagaaaggctaaaagccacattaacaaagaaggaaagctttctgcacat cacagcccctaaacctgaagactcagccacttatctctgt SEQ ID NO: 386 TRAV20*04-5′ gaagaccaggtgacgcagagtcccgaggccctgagactccaggagggagagagtagcagt ctcaactgcagttgcacagtcagcggtttaagagggctgt SEQ ID NO: 387 TRAV20*04-3′ aaaggagaaagaaaggctaaaagccacattaacaaagaaggaaagctttctgcacatcac agcccctaaacctgaagactcagccacttatctctgtgct SEQ ID NO: 388 TRAV21*01-5′ aaacaggaggtgacgcagattcctgcagctctgagtgtcccagaaggagaaaacttggtt ctcaactgcagtttcactgatagcgctatttacaacctcc SEQ ID NO: 389 TRAV21*01-3′ aagacttaatgcctcgctggataaatcatcaggacgtagtactttatacattgcagcttc tcagcctggtgactcagccacctacctctgtgctgtgagg SEQ ID NO: 390 TRAV21*02-5′ aaacaggaggtgacacagattcctgcagctctgagtgtcccagaaggagaaaacttggtt ctcaactgcagtttcactgatagcgctatttacaacctcc SEQ ID NO: 391 TRAV21*02-3′ aagtggaagacttaatgcctcgctggataaatcatcaggacgtagtactttatacattgc agcttctcagcctggtgactcagccacctacctctgtgct SEQ ID NO: 392 TRAV22*01-5′ ggaatacaagtggagcagagtcctccagacctgattctccaggagggagccaattccacg ctgcggtgcaatttttctgactctgtgaacaatttgcagt SEQ ID NO: 393 TRAV22*01-3′ agattaagcgccacgactgtcgctacggaacgctacagcttattgtacatttcctcttcc cagaccacagactcaggcgtttatttctgtgctgtggagc SEQ ID NO: 394 TRAV23/DV6*01-5′ cagcagcaggtgaaacaaagtcctcaatctttgatagtccagaaaggagggatttcaatt ataaactgtgcttatgagaacactgcgtttgactactttc SEQ ID NO: 395 TRAV23/DV6*01-3′ agattcacaatctccttcaataaaagtgccaagcagttctcattgcatatcatggattcc cagcctggagactcagccacctacttctgtgcagcaagca SEQ ID NO: 396 TRAV23/DV6*02-5′ cagcagcaggtgaaacaaagtcctcaatctttgatagtccagaaaggagggattccaatt ataaactgtgcttatgagaacactgcgtttgactactttc SEQ ID NO: 397 TRAV23/DV6*02-3′ agattcacaatctccttcaataaaagtgccaagcagttctcattgcatatcatggattcc cagcctggagactcagccacctacttctgtgcagcaagcg SEQ ID NO: 398 TRAV23/DV6*03-5′ cagcagcaggtgaaacaaagtcctcaatctttgatagtccagaaaggagggatttcaatt ataaactgtgcttatgagaacactgcgtttgactactttc SEQ ID NO: 399 TRAV23/DV6*03-3′ agattcacaatctccttcaataaaagtgccaagcagttctcattgcatatcatggattcc cagcctggagactcagccacctacttctgtgcagcaagca SEQ ID NO: 400 TRAV23/DV6*04-5′ cagcaggtgaaacaaagtcctcaatctttgatagtccagaaaggagggatttcaattata aactgtgcttatgagaacactgcgtttgactactttccat SEQ ID NO: 401 TRAV23/DV6*04-3′ gaaagaaggaagattcacaatctccttcaataaaagtgccaagcagttctcattgcatat catggattcccagcctggagactcagccacctacttctgt SEQ ID NO: 402 TRAV24*01-5′ aggacgaataagtgccactcttaataccaaggagggttacagctatttgtacatcaaagg atcccagcctgaagactcagccacatacctctgtgccttt SEQ ID NO: 403 TRAV24*01-3′ ggacgaataagtgccactcttaataccaaggagggttacagctatttgtacatcaaagga tcccagcctgaagactcagccacatacctctgtgccttta SEQ ID NO: 404 TRAV24*02-5′ atactgaacgtggaacaaggtcctcagtcactgcatgttcaggagggagacagcaccaat ttcacctgcagcttcccttccagcaatttttatgccttac SEQ ID NO: 405 TRAV24*02-3′ ggacgaataagtgccactcttaataccaaggagggttacagctatttgtacatcaaagga tcccagcctgaagattcagccacatacctctgtgccttta SEQ ID NO: 406 TRAV25*01-5′ ggacaacaggtaatgcaaattcctcagtaccagcatgtacaagaaggagaggacttcacc acgtactgcaattcctcaactactttaagcaatatacagt SEQ ID NO: 407 TRAV25*01-3′ gaaaagactgacatttcagtttggagaagcaaaaaagaacagctccctgcacatcacagc cacccagactacagatgtaggaacctacttctgtgcaggg SEQ ID NO: 408 TRAV26-1*01-5′ gatgctaagaccacccagcccccctccatggattgcgctgaaggaagagctgcaaacctg ccttgtaatcactctaccatcagtggaaatgagtatgtgt SEQ ID NO: 409 TRAV26-1*01-3′ gcctctctgatcatcacagaagacagaaagtccagcaccttgatcctgccccacgctacg ctgagagacactgctgtgtactattgcatcgtcagagtcg SEQ ID NO: 410 TRAV26-1*02-5′ gatgctaagaccacccagcccacctccatggattgcgctgaaggaagagctgcaaacctg ccttgtaatcactctaccatcagtggaaatgagtatgtgt SEQ ID NO: 411 TRAV26-1*02-3′ ctctgatcatcacagaagacagaaagtccagcaccttgatcctgccccacgctacgctga gagacactgctgtgtactattgcatcgtcagagattgggt SEQ ID NO: 412 TRAV26-1*03-5′ gatgctaagaccacccagcccccctccatggattgcgctgaaggaagagctgcaaacctg ccttgtaatcactctaccatcagtggaaatgagtatgtgt SEQ ID NO: 413 TRAV26-1*03-3′ caatgaaatggcctctctgatcatcacagaagacagaaagtccagcaccttgatcctgcc ccacgctacgctgagagacactgctgtgtactattgcatc SEQ ID NO: 414 TRAV26-2*01-5′ gatgctaagaccacacagccaaattcaatggagagtaacgaagaagagcctgttcacttg ccttgtaaccactccacaatcagtggaactgattacatac SEQ ID NO: 415 TRAV26-2*01-3′ ggcctctctggcaatcgctgaagacagaaagtccagtaccttgatcctgcaccgtgctac cttgagagatgctgctgtgtactactgcatcctgagagac SEQ ID NO: 416 TRAV26-2*02-5′ gatgctaagaccacacagccaaattcaatggagagtaacgaagaagagcctgttcacttg ccttgtaaccactccacaatcagtggaactgattacatac SEQ ID NO: 417 TRAV26-2*02-3′ ccctcccagggtccagagtacgtgattcatggtcttacaagcaatgtgaacaacagaatg gcctgtgtggcaatcgctgaagacagaaagtccagtacct SEQ ID NO: 418 TRAV27*01-5′ acccagctgctggagcagagccctcagtttctaagcatccaagagggagaaaatctcact gtgtactgcaactcctcaagtgttttttccagcttacaat SEQ ID NO: 419 TRAV27*01-3′ aagagactaacctttcagtttggtgatgcaagaaaggacagttctctccacatcactgca gcccagcctggtgatacaggcctctacctctgtgcaggag SEQ ID NO: 420 TRAV27*02-5′ acccagctgctggagcagagccctcagtttctaagcatccaagagggagaaaatctcact gtgtactgcaactcctcaagtgttttttccagcttacaat SEQ ID NO: 421 TRAV27*02-3′ tgaagagactaacctttcagtttggtgatgcaagaaaggacagttctctccacatcactg cggcccagcctggtgatacaggccactacctctgtgcagg SEQ ID NO: 422 TRAV27*03-5′ acccagctgctggagcagagccctcagtttctaagcatccaagagggagaaaatctcact gtgtactgcaactcctcaagtgttttttccagcttacaat SEQ ID NO: 423 TRAV27*03-3′ gctgaagagactaacctttcagtttggtgatgcaagaaaggacagttctctccacatcac tgcagcccagactggtgatacaggcctctacctctgtgca SEQ ID NO: 424 TRAV28*01-5′ aaagtggagcagagtcctcaggtcctgatcctccaagagggaagaaattcattcctggtg tgcagttgttctatttacatgatccgtgtgcagtggtttc SEQ ID NO: 425 TRAV27*01-3′ gaagactaaaatccgcagtcaaagctgaggaactttatggccacctatacatcagattcc cagcctgaggactcagctatttacttctgtgctgtgggga SEQ ID NO: 426 TRAV29/DV5*01-5′ gaccagcaagttaagcaaaattcaccatccctgagcgtccaggaaggaagaatttctatt ctgaactgtgactatactaacagcatgtttgattatttcc SEQ ID NO: 427 TRAV29/DV5*01-3′ agattcactgtcttcttaaacaaaagtgccaagcacctctctctgcacattgtgccctcc cagcctggagactctgcagtgtacttctgtgcagcaagcg SEQ ID NO: 428 TRAV29/DV5*02-5′ gaccagcaagttaagcaaaattcaccatccctgagcgtccaggaaggaagaatttctatt ctgaactgtgactatactaacagcatgtttgattatttcc SEQ ID NO: 429 TRAV29/DV5*02-3′ aagattcactgttttcttaaacaaaagtgccaagcacctctctctcgacattgtgccctc ccagcctggagactctgcagtgtacttctgtgcagcaagc SEQ ID NO: 430 TRAV29/DV5*03-5′ gaccagcaagttaagcaaaattcaccatccctgagcgtccaggaaggaagaatttctatt ctgaactgtgactatactaacagcatgtttgattatttcc SEQ ID NO: 431 TRAV29/DV5*03-3′ agattcactgttttcttaaacaaaagtgccaagcacctctctctgcacattgtgccctcc cagcctggagactctgcagtgtacttctgtgcagcaagcg SEQ ID NO: 432 TRAV3*01-5′ gctcagtcagtggctcagccggaagatcaggtcaacgttgctgaagggaatcctctgact gtgaaatgcacctattcagtctctggaaacccttatcttt SEQ ID NO: 433 TRAV3*01-3′ tttgaagctgaatttaacaagagccaaacctccttccacctgaagaaaccatctgccctt gtgagcgactccgctttgtacttctgtgctgtgagagaca SEQ ID NO: 434 TRAV3*02-5′ gctcagtcagtggctcagcggaagatcaggtcaacgttgctgaagggaatcctctgactg tgaaatgcacctattcagtctctggaaacccttatctttt SEQ ID NO: 435 TRAV3*02-3′ ctttgaagctgaatttaacaagagccaaacctccttccacctgaagaaaccatctgccct tgtgagcgactccgctttgtacttctgtgctgtgagaccc SEQ ID NO: 436 TRAV30*01-5′ caacaaccagtgcagagtcctcaagccgtgatcctccgagaaggggaagatgctgtcatc aactgcagttcctccaaggctttatattctgtacactggt SEQ ID NO: 437 TRAV30*01-3′ aaaatatctgcttcatttaatgaaaaaaagcagcaaagctccctgtaccttacggcctcc cagctcagttactcaggaacctacttctgcggcacagaga SEQ ID NO: 438 TRAV30*02-5′ caacaaccagtgcagagtcctcaagccgtgatcctccgagaaggggaagatgctgtcacc aactgcagttcctccaaggctttatattctgtacactggt SEQ ID NO: 439 TRAV30*02-3′ tcgtgaaaaaatatctgcttcatttaatgaaaaaaagcagcaaagctccctgtaccttac ggcctcccagctcagttactcaggaacctacttctgcggg SEQ ID NO: 440 TRAV30*03-5′ caacaaccagtgcagagtcctcaagccgtgatcctccgagaaggggaagatgctgtcatc aactgcagttcctccaaggctttatattctgtacactggt SEQ ID NO: 441 TRAV30*03-3′ tcatgaaaaaatatctgcttcatttaatgaaaaaaagcggcaaagctccctgtaccttac ggcctcccagctcagttactcaggaacctacttctgcggc SEQ ID NO: 442 TRAV30*04-5′ caacaaccagtgcagagtcctcaagccgtgatcctccgagaaggggaagatgctgtcatc aactgcagttcctccaaggctttatattctgtacactggt SEQ ID NO: 443 TRAV30*04-3′ tcctgatgatattactgaagggtggagaacagaagcgtcatgaaaaaatatctgcttcat ttaatgaaaaaaagcagcaaagctccctgtaccttacggc SEQ ID NO: 444 TRAV31*01-5′ cagagggtcattcaatcccaaccagcaatatctacgcaggagggtgagaccgtgaaactg gactgtgcatacaaaactaatattgtatattacatattgt SEQ ID NO: 445 TRAV31*01-3′ tattctgtgagcttccagaaaacaactaaaactattcagcttatcatatcatcatcacag ccagaagacctgcaacatatttctgttgtctcaaagagcc SEQ ID NO: 446 TRAV32*01-5′ aaggatgtgatacagagttattcaaatctaaatgtctaggagagagaaatggccgttatt aatgacagttatacagatggagctttgaattatttctgtt SEQ ID NO: 447 TRAV32*01-3′ aggctcactgtactgttgaataaaaatgctaaacatgtctccctgcatattacagccacc caaccaggagactcattcctgtacttctgtgcagtgagaa SEQ ID NO: 448 TRAV33*01-5′ gctcagaaagtaacccaagttcagaccacagtaactaggcagaaaggagtagctgtgacc ttggactgcatgtttgaaaccagatagaattcgtacactt SEQ ID NO: 449 TRAV33*01-3′ gcaaagcctgtgaactttgaaaaaaagaaaaagttcatcaacctcaccatcaattcctta aaactgactcagccaagtacttctgtgctctcaggaatcc SEQ ID NO: 450 TRAV34*01-5′ agccaagaactggagcagagtcctcagtccttgatcgtccaagagggaaagaatctcacc ataaactgcacgtcatcaaagacgttatatggcttatact SEQ ID NO: 451 TRAV34*01-3′ aagataactgccaagttggatgagaaaaagcagcaaagttccctgcatatcacagcctcc cagcccagccatgcaggcatctacctctgtggagcagaca SEQ ID NO: 452 TRAV35*01-5′ ggtcaacagctgaatcagagtcctcaatctatgtttatccaggaaggagaagatgtctcc atgaactgcacttcttcaagcatatttaacacctggctat SEQ ID NO: 453 TRAV35*01-3′ aagactgactgctcagtttggtataaccagaaaggacagcttcctgaatatctcagcatc catacctagtgatgtaggcatctacttctgtgctgggcag SEQ ID NO: 454 TRAV35*02-5′ ggtcaacagctgaatcagagtcctcaatctatgtttatccaggaaggagaagatgtctcc atgaactgcacttcttcaagcatatttaacacctggctat SEQ ID NO: 455 TRAV35*02-3′ aaatggaagactgactgctcagtttggtataaccagaaaggacagcttcctgaatatctc agcatccatacctagtgatgtaggcatctacttctgtgct SEQ ID NO: 456 TRAV36/DV7*01-5′ gaagacaaggtggtacaaagccctctatctctggttgtccacgagggagacaccgtaact ctcaattgcagttatgaagtgactaactttcgaagcctac SEQ ID NO: 457 TRAV36/DV7*01-3′ agactaagtagcatattagataagaaagaactttccagcatcctgaacatcacagccacc cagaccggagactcggccatctacctctgtgctgtggagg SEQ ID NO: 458 TRAV36/DV7*02-5′ gaagacaaggtggtacaaagccctcaatctctggttgtccacgagggagacactgtaact ctcaattgcagttatgaaatgactaactttcgaagcctac SEQ ID NO: 459 TRAV36/DV7*02-3′ ggaagactaagtagcatattagataagaaagaacttttcagcatcctgaacatcacagcc acccagaccggagactcggccgtctacctctgtgctgtgg SEQ ID NO: 460 TRAV36/DV7*03-5′ gaagacaaggtggtacaaagccctctatctctggttgtccacgagggagacactgtaact cccaattgcagttatgaagtgactaactttcgaagcctac SEQ ID NO: 461 TRAV36/DV7*03-3′ gtcaggaagactaagtagcatattagataagaaagaacttttcagcatcctgaacatcac agccacccagaccggagactcggccgtctacctctgtgct SEQ ID NO: 462 TRAV36/DV7*04-5′ gaagacaaggtggtacaaagccctctatctctggttgtccacgagggagacactgtaact ctcaattgcagttatgaagtgactaactttcgaagcctac SEQ ID NO: 463 TRAV36/DV7*04-3′ tcaggaagactaagtagcatattagataagaaagaacttttcagcatcctgaacatcaca gccacccagaccggagactcggccgtctacctctgtgctg SEQ ID NO: 464 TRAV37*01-5′ caactgccagtggaacagaatgctccttccctgaaagtcaaggaaggtgacagcgtcaca ctgaactgcagttacagagacagcccttcagatttcttca SEQ ID NO: 465 TRAV37*01-3′ agattcacagccaggcttaaaaaaggagaccagcacatttccctgcacatacaggattcc cagctccatgactcaaccacattcttctgcgcagcaagca SEQ ID NO: 466 TRAV38-1*01-5′ gcccagacagtcactcagtctcaaccagagatgtctgtgcaggaggcagagactgtgacc ctgagttgcacatatgacaccagtgagaataattattatt SEQ ID NO: 467 TRAV38-1*01-3′ tctctgtgaacttccagaaagcagccaaatccttcagtctcaagatctcagactcacagc tgggggacactgcgatgtatttctgtgctttcatgaagca SEQ ID NO: 468 TRAV38-1*02-5′ gcccagacagtcactcagtctcaaccagagatgtctgtgcaggaggcagagactgtgacc ctgagttgcacatatgacaccagtgagaatgattattatt SEQ ID NO: 469 TRAV38-1*02-3′ gagaatcgtttctctgtgaacttccagaaagcagccaaatccttcagtctcaagatctca gactcacagctgggggacactgcgatgtatttctgtgctt SEQ ID NO: 470 TRAV38-1*03-5′ gcccagacagtcactcagtctcaaccagagatgtctgtgcaggaggcagagactgtgacc ctgagttgcacatatgacaccagtgagagtaattattatt SEQ ID NO: 471 TRAV38-1*03-3′ aatcgtttctctgtgaacttccagaaagcagccaaatccttcagtctcaagatctcagac tcacagctgggggacactgcgatgtatttctgtgctttca SEQ ID NO: 472 TRAV38-1*04-5′ gcccagacagtcactcagtcccagccagagatgtctgtgcaggaggcagagactgtgacc ctgagttgcacatatgacaccagtgagaataattattatt SEQ ID NO: 473 TRAV38-1*04-3′ ggagaatcgtttctctgtgaacttccagaaagcagccaaatccttcagtctcaagatctc agactcacagctgggggacactgcgatgtatttctgtgca SEQ ID NO: 474 TRAV38-2/DV8*01-5′ gctcagacagtcactcagtctcaaccagagatgtctgtgcaggaggcagagaccgtgacc ctgagctgcacatatgacaccagtgagagtgattattatt SEQ ID NO: 475 TRAV38-2/DV8*01-3′ ttctctgtgaacttccagaaagcagccaaatccttcagtctcaagatctcagactcacag ctgggggatgccgcgatgtatttctgtgcttataggagcg SEQ ID NO: 476 TRAV39*01-5′ gagctgaaagtggaacaaaaccctctgttcctgagcatgcaggagggaaaaaactatacc atctactgcaattattcaaccacttcagacagactgtatt SEQ ID NO: 477 TRAV39*01-3′ cgattaatggcctcacttgataccaaagcccgtctcagcaccctccacatcacagctgcc gtgcatgacctctctgccacctacttctgtgccgtggaca SEQ ID NO: 478 TRAV4*01-5′ cttgctaagaccacccagcccatctccatggactcatatgaaggacaagaagtgaacata acctgtagccacaacaacattgctacaaatgattatatca SEQ ID NO: 479 TRAV4*01-3′ gcctccctgtttatccctgccgacagaaagtccagcactctgagcctgccccgggtttcc ctgagcgacactgctgtgtactactgcctcgtgggtgaca SEQ ID NO: 480 TRAV40*01-5′ agcaattcagtcaagcagacgggccaaataaccgtctcggagggagcatctgtgactatg aactgcacatacacatccacggggtaccctacccttttct SEQ ID NO: 481 TRAV40*01-3′ aaaacttcggaggcggaaatattaaagacaaaaactcccccattgtgaaatattcagtcc aggtatcagactcagccgtgtactactgtcttctgggaga SEQ ID NO: 482 TRAV41*01-5′ aaaaatgaagtggagcagagtcctcagaacctgactgcccaggaaggagaatttatcaca atcaactgcagttactcggtaggaataagtgccttacact SEQ ID NO: 483 TRAV41*01-3′ aagattaattgccacaataaacatacaggaaaagcacagctccctgcacatcacagcctc ccatcccagagactctgccgtctacatctgtgctgtcaga SEQ ID NO: 484 TRAV5*01-5′ ggagaggatgtggagcagagtcttttcctgagtgtccgagagggagacagctccgttata aactgcacttacacagacagctcctccacctacttatact SEQ ID NO: 485 TRAV5*01-3′ agactcactgttctattgaataaaaaggataaacatctgtctctgcgcattgcagacacc cagactggggactcagctatctacttctgtgcagagagta SEQ ID NO: 486 TRAV6*01-5′ agccaaaagatagaacagaattccgaggccctgaacattcaggagggtaaaacggccacc ctgacctgcaactatacaaactattccccagcatacttac SEQ ID NO: 487 TRAV6*01-3′ agactgaaggtcacctttgataccacccttaaacagagtttgtttcatatcacagcctcc cagcctgcagactcagctacctacctctgtgctctagaca SEQ ID NO: 488 TRAV6*02-5′ agccaaaagatagaacagaattccgaggccctgaacattcaggagggtaaaacggccacc ctgacctgcaactatacaaactattctccagcatacttac SEQ ID NO: 489 TRAV6*02-3′ gaaagaaagactgaaggtcacctttgataccacccttaaacagagtttgtttcatatcac agcctcccagcctgcagactcagctacctacctctgtgct SEQ ID NO: 490 TRAV6*03-5′ gaggccctgaacattcaggagggtaaaacggccaccctgacctgcaactatacaaactat tctccagcatacttacagtggtaccgacaagatccaggaa SEQ ID NO: 491 TRAV6*03-3′ gaaagaaagactgaaggtcacctttgataccacccttaaacagagtttgtttcatatcac agcctcccagcctgcagactcagctacctacctctgtgct SEQ ID NO: 492 TRAV6*04-5′ gaggccctgaacattcaggagggtaaaacggccaccctgacctgcaactatacaaactat tctccagcatacttacagtggtaccgacaagatccaggaa SEQ ID NO: 493 TRAV6*04-3′ gaaagaaagactgaaggtcacctttgataccacccttaaacagagtttgtttcatgtcac agcctcccagcctgcagactcagctacctacctctgtgct SEQ ID NO: 494 TRAV6*05-5′ gaggccctgaacattcaggagggtaaaacggccaccctgacctgcaactatacgaactat tctccagcatacttacagtggtaccgacaagatccaggaa SEQ ID NO: 495 TRAV6*05-3′ gaaagaaagactgaaggtcacctttgataccacccttaaacagagtttgtttcatatcac agcctcccagcctgcagactcagctacctacctctgtgct SEQ ID NO: 496 TRAV6*06-5′ agccaaaagatagaacagaattccgaggccctgaacattcaggagggtaaaacggccacc ctgacctgcaactatacaaactattctccagcatacttac SEQ ID NO: 497 TRAV6*06-3′ ccaggaagaggccctgttttcttgctactcatacgtgaaaatgagaaagaaaaaaggaaa gaaagactgaaggtcacctttgataccacccttaaccaga SEQ ID NO: 498 TRAV7*01-5′ gaaaaccaggtggagcacagccctcattttctgggaccccagcagggagacgttgcctcc atgagctgcacgtactctgtcagtcgttttaacaatttgc SEQ ID NO: 499 TRAV7*01-3′ aaaggaagactaaatgctacattactgaagaatggaagcagcttgtacattacagccgtg cagcctgaagattcagccacctatttctgtgctgtagatg SEQ ID NO: 500 TRAV8-1*01-5′ gcccagtctgtgagccagcataaccaccacgtaattctctctgaagcagcctcactggag ttgggatgcaactattcctatggtggaactgttaatctct SEQ ID NO: 501 TRAV8-1*01-3′ gctttgaggctgaatttataaagagtaaattctcctttaatctgaggaaaccctctgtgc agtggagtgacacagctgagtacttctgtgccgtgaatgc SEQ ID NO: 502 TRAV8-1*02-5′ gcccagtctgtgagccagcataaccaccacgtaattctctctgaagcagcctcactggag ttgggatgcaactattcctatggtggaactgttaatctct SEQ ID NO: 503 TRAV8-1*02-3′ ttttcaggggatccactggttaaaggcatcaagggcgttgaggctgaatttataaagagt aaattctcctttaatctgaggaaaccctctgtgcagtgga SEQ ID NO: 504 TRAV8-2*01-5′ gcccagtcggtgacccagcttgacagccacgtctctgtctctgaaggaaccccggtgctg ctgaggtgcaactactcatcttcttattcaccatctctct SEQ ID NO: 505 TRAV8-2*01-3′ gttttgaggctgaatttaagaagagtgaaacctccttccacctgacgaaaccctcagccc atatgagcgacgcggctgagtacttctgtgttgtgagtga SEQ ID NO: 506 TRAV8-2*02-5′ gcccagtcggtgacccagcttagcagccacgtctctgtctctgaaggaaccccggtgctg ctgaggtgcaactactcatcttcttattcaccatctctct SEQ ID NO: 507 TRAV8-2*02-3′ tttaagaagagtgaaacctccttccacctgacgaaaccctcagcccatatgagcgacgcg gctgagtacttctgtgttgtgacccgtcacgagctttcag SEQ ID NO: 508 TRAV8-3*01-5′ gcccagtcagtgacccagcctgacatccacatcactgtctctgaaggagcctcactggag ttgagatgtaactattcctatggggcaacaccttatctct SEQ ID NO: 509 TRAV8-3*01-3′ gctttgaggctgaatttaagaggagtcaatcttccttcaatctgaggaaaccctctgtgc attggagtgatgctgctgagtacttctgtgctgtgggtgc SEQ ID NO: 510 TRAV8-3*02-5′ gcccagtcagtgacccagcctgacatccacatcactgtctctgaaggagcctcactggag ttgagatgtaactattcctatgggcaaacaccttatctct SEQ ID NO: 511 TRAV8-3*02-3′ aggctttgaggctgaatttaagaggagtcaatcttccttcaacctgaggaaaccctctgt gcattggagtgatgctgctgagtacttctgtgctgtggtt SEQ ID NO: 512 TRAV8-3*03-5′ gcccagtcagtgacccagcctgacatccacatcactgtctctgaaggagcctcactggag ttgagatgtaactattcctatggggcaacaccttatctct SEQ ID NO: 513 TRAV8-3*03-3′ tattaaaggctttgaggctgaatttaagaggagtcaatcttccttcaatctgaggaaacc ctctgtgcattggagtgatgcgtctgagtacttctgtgct SEQ ID NO: 514 TRAV8-4*01-5′ gcccagtcggtgacccagcttggcagccacgtctctgtctctgaaggagccctggttctg ctgaggtgcaactactcatcgtctgttccaccatatctct SEQ ID NO: 515 TRAV8-4*01-3′ gttttgaggctgaatttaagaagagtgaaacctccttccacctgacgaaaccctcagccc atatgagcgacgcggctgagtacttctgtgctgtgagtga SEQ ID NO: 516 TRAV8-4*02-5′ gcccagtcggtgacccagcttggcagccacgtctctgtctctgaaggagccctggttctg ctgaggtgcaactactcatcgtctgttccaccatatctct SEQ ID NO: 517 TRAV8-4*02-3′ gaatttaagaagagtgaaacctccttccacctgacaaaaccctcagcccatatgagcgac gcggctgagtacttctgtgctgtgagtgatctcgaaccga SEQ ID NO: 518 TRAV8-4*03-5′ gcccagtcggtgacccagcttggcagccacgtctctgtctctgagggagccctggttctg ctgaggtgcaactactcatcgtctgttccaccatatctct SEQ ID NO: 519 TRAV8-4*03-3′ catcaacggttttgaggctgaatttaagaagagtgaaacctccttccacctgacgaaacc ctcagcccatatgagcgacgcggctgagtacttctgtgct SEQ ID NO: 520 TRAV8-4*04-5′ gcccagtcggtgacccagcttggcagccacgtctctgtctctgaacgagccctggttctg ctgaggtgcaactactcatcgtctgttccaccatatctct SEQ ID NO: 521 TRAV8-4*04-3′ aggcatcaacggttttgaggctgaatttaagaagagtgaaacctccttccacctgacgaa accctcagcccatatgagcgacgcggctgagtacttctgt SEQ ID NO: 522 TRAV8-4*05-5′ gcccagtcggtgacccagcttggcagccacgtctctgtctctgaaggagccctggttctg ctgaggtgcaactactcatcgtctgttccaccatatctct SEQ ID NO: 523 TRAV8-4*05-3′ ggctgaatttaagaagagtgaaacctccttccacctgacgaaaccctcagcccatatgag cgacgcggctgagtacttctgtgctgtgagtgagtctcca SEQ ID NO: 524 TRAV8-4*06-5′ ctcttctggtatgtgcaataccccaaccaaggactccagcttctcctgaagtacacatca gcggccaccctggttaaaggcatcaacggttttgaggctg SEQ ID NO: 525 TRAV8-4*06-3′ gaatttaagaagagtgaaacctccttccacctgacgaaacccgcagcccatatgagcgac gcggctgagtacttctgtgctgtgagtgatctcgaaccga SEQ ID NO: 526 TRAV8-4*07-5′ gttgaaccatatctcttctggtatgtgcaataccccaaccaaggactccagcttctcctg aagtacacaacaggggccaccctggttaaaggcatcaacg SEQ ID NO: 527 TRAV8-4*07-3′ acggttttgaggctgaatttaaaaagagtgaaacctccttccacctgacgaaaccctcag cccatatgaccgacccggctgagtacttctgtgctgtgag SEQ ID NO: 528 TRAV8-5*01-5′ gcccagtcagtgacccagcctgacatccgcatcactgtctctgaaggagcctcactggag ttgagatgtaactattcctatggggcgatgttgtgggaag SEQ ID NO: 529 TRAV8-5*01-3′ tggacacttatcacttccccaatcaatacccctgtgatttcctatgcctgtctttacttt aatctcttaatcctgtcagctgaggaggatgtatgtcacc SEQ ID NO: 530 TRAV8-6*01-5′ gcccagtctgtgacccagcttgacagccaagtccctgtctttgaagaagcccctgtggag ctgaggtgcaactactcatcgtctgtttcagtgtatctct SEQ ID NO: 531 TRAV8-6*01-3′ gttttgaggctgaatttaacaagagtcaaacttccttccacttgaggaaaccctcagtcc atataagcgacacggctgagtacttctgtgctgtgagtga SEQ ID NO: 532 TRAV8-6*02-5′ gcccagtctgtgacccagcttgacagccaagtccctgtctttgaagaagcccctgtggag ctgaggtgcaactactcatcgtctgtttcagtgtatctct SEQ ID NO: 533 TRAV8-6*02-3′ gttttgaggctgaatttaacaagagtcaaacttccttccacttgaggaaaccctcagtcc atataagcgacacggctgagtacttctgtgctgtgagtga SEQ ID NO: 534 TRAV8-7*01-5′ acccagtcggtgacccagcttgatggccacatcactgtctctgaagaagcccctctggaa ctgaagtgcaactattcctatagtggagttccttctctct SEQ ID NO: 535 TRAV8-7*01-3′ aggctgaatttaagaagagcgaaacctccttctacctgaggaaaccatcaacccatgtga gtgatgctgctgagtacttctgtgctgtgggtgacaggag SEQ ID NO: 536 TRAV9-1*01-5′ ggagattcagtggtccagacagaaggccaagtgctcccctctgaaggggattccctgatt gtgaactgctcctatgaaaccacacagtacccttcccttt SEQ ID NO: 537 TRAV9-1*01-3′ gttttgaagccatgtaccgtaaagaaaccacttctttccacttggagaaagactcagttc aagagtcagactccgctgtgtacttctgtgctctgagtga SEQ ID NO: 538 TRAV9-2*01-5′ ggaaattcagtgacccagatggaagggccagtgactctctcagaagaggccttcctgact ataaactgcacgtacacagccacaggatacccttcccttt SEQ ID NO: 539 TRAV9-2*01-3′ gttttgaagccacataccgtaaagaaaccacttctttccacttggagaaaggctcagttc aagtgtcagactcagcggtgtacttctgtgctctgagtga SEQ ID NO: 540 TRAV9-2*02-5′ ggagattcagtgacccagatggaagggccagtgactctctcagaagaggccttcctgact ataaactgcacgtacacagccacaggatacccttcccttt SEQ ID NO: 541 TRAV9-2*02-3′ caacaaaggttttgaagccacataccgtaaagaaaccacttctttccacttggagaaagg ctcagttcaagtgtcagactcagcggtgtacttctgtgct SEQ ID NO: 542 TRAV9-2*03-5′ ggagattcagtgacccagatggaagggccagtgactctctcagaagaggccttcctgact ataaactgcacgtacacagccacaggatacccttcccttt SEQ ID NO: 543 TRAV9-2*03-3′ caacaaaggttttgaagccacataccgtaaggaaaccacttctttccacttggagaaagg ctcagttcaagtgtcagactcagcggtgtacttctgtgct SEQ ID NO: 544 TRAV9-2*04-5′ ggaaattcagtgacccagatggaagggccagtgactctctcagaagaggccttcctgact ataaactgcacgtacacagccacaggatacccttcccttt SEQ ID NO: 545 TRAV9-2*04-3′ caacaaaggttttgaagccacataccgtaaggaaaccacttctttccacttggagaaagg ctcagttcaagtgtcagactcagcggtgtacttctgtgct SEQ ID NO: 546 TRBV1*01-5′ gatactggaattacccagacaccaaaatacctggtcacagcaatggggagtaaaaggaca atgaaacgtgagcatctgggacatgattctatgtattggt SEQ ID NO: 547 TRBV1*01-3′ acttcacacctgaatgccctgacagctctcgcttataccttcatgtggtcgcactgcagc aagaagactcagctgcgtatctctgcaccagcagccaaga SEQ ID NO: 548 TRBV10-1*01-5′ gatgctgaaatcacccagagcccaagacacaagatcacagagacaggaaggcaggtgacc ttggcgtgtcaccagacttggaaccacaacaatatgttct SEQ ID NO: 549 TRBV10-1*01-3′ gctacagtgtctctagatcaaacacagaggacctccccctcactctggagtctgctgcct cctcccagacatctgtatatttctgcgccagcagtgagtc SEQ ID NO: 550 TRBV10-1*02-5′ gatgctgaaatcacccagagcccaagacacaagatcacagagacaggaaggcaggtgacc ttggcgtgtcaccagacttggaaccacaacaatatgttct SEQ ID NO: 551 TRBV10-1*02-3′ agatggctacagtgtctctagatcaaacacagaggacctccccctcactctggagtctgc tgcctcctcccagacatctgtatatttctgcgccagcagt SEQ ID NO: 552 TRBV10-1*03-5′ aggcaggtgaccttggcgtgtcaccagacttggaaccacaacaatatgttctggtatcga caagacctgggacatgggctgaggctgatccattactcat SEQ ID NO: 553 TRBV10-1*03-3′ ctaacaaaggagaagtctcagatggctacagtgtctctagatcaaacacagaggacctcc ccctcactctgtagtctgctgcctcctcccagacatctgt SEQ ID NO: 554 TRBV10-2*01-5′ gatgctggaatcacccagagcccaagatacaagatcacagagacaggaaggcaggtgacc ttgatgtgtcaccagacttggagccacagctatatgttct SEQ ID NO: 555 TRBV10-2*01-3′ gctatgttgtctccagatccaagacagagaatttccccctcactctggagtcagctaccc gctcccagacatctgtgtatttctgcgccagcagtgagtc SEQ ID NO: 556 TRBV10-2*02-5′ aaggcaggtgaccttgatgtgtcaccagacttggagccacagctatatgttctggtatcg acaagacctgggacatgggctgaggctgatctattactca SEQ ID NO: 557 TRBV10-2*02-3′ agataaaggagaagtccccgatggctacgttgtctccagatccaagacagagaatttccc cctcactctggagtcagctacccgctcccagacatctgtg SEQ ID NO: 558 TRBV10-3*01-5′ gatgctggaatcacccagagcccaagacacaaggtcacagagacaggaacaccagtgact ctgagatgtcaccagactgagaaccaccgctatatgtact SEQ ID NO: 559 TRBV10-3*01-3′ gctatagtgtctctagatcaaagacagaggatttcctcctcactctggagtccgctacca gctcccagacatctgtgtacttctgtgccatcagtgagtc SEQ ID NO: 560 TRBV10-3*02-5′ gatgctggaatcacccagagcccaagacacaaggtcacagagacaggaacaccagtgact ctgagatgtcatcagactgagaaccaccgctatatgtact SEQ ID NO: 561 TRBV10-3*02-3′ gctatagtgtctctagatcaaagacagaggatttcctcctcactctggagtccgctacca gctcccagacatctgtgtacttctgtgccatcagtgagtc SEQ ID NO: 562 TRBV10-3*03-5′ gatgctggaatcacccagagcccaagacacaaggtcacagagacaggaacaccagtgact ctgagatgtcaccagactgagaaccaccgctacatgtact SEQ ID NO: 563 TRBV10-3*03-3′ agaagtctcagatggctatagtgtctctagatcaaagacagaggatttcctcctcactct ggagtccgctaccagctcccagacatctgtgtacttctgt SEQ ID NO: 564 TRBV10-3*04-5′ gatgctggaatcacccagagcccaagacacaaggtcacagagacaggaacaccagtgact ctgagatgtcaccagactgagaaccaccgctacatgtact SEQ ID NO: 565 TRBV10-3*04-3′ agaagtctcagatggctatagtgtctctagatcaaagacagaggatttcctcctcactct ggagtccgctaccagctcccagacatctgtgtacttctgt SEQ ID NO: 566 TRBV11-1*01-5′ gaagctgaagttgcccagtcccccagatataagattacagagaaaagccaggctgtggct ttttggtgtgatcctatttctggccatgctaccctttact SEQ ID NO: 567 TRBV11-1*01-3′ gattttctgcagagaggctcaaaggagtagactccactctcaagatccagcctgcagagc ttggggactcggccatgtatctctgtgccagcagcttagc SEQ ID NO: 568 TRBV11-2*01-5′ gaagctggagttgcccagtctcccagatataagattatagagaaaaggcagagtgtggct ttttggtgcaatcctatatctggccatgctaccctttact SEQ ID NO: 569 TRBV11-2*01-3′ gattttctgcagagaggctcaaaggagtagactccactctcaagatccagcctgcaaagc ttgaggactcggccgtgtatctctgtgccagcagcttaga SEQ ID NO: 570 TRBV11-2*02-5′ gaagctggagttgcccagtctcccagatataagattatagagaaaaggcagagtgtggct ttttggtgcaatcctatatctggccatgctaccctttact SEQ ID NO: 571 TRBV11-2*02-3′ ggatcgattttctgcagagaggctcaaaggagtagactccactctcaagatccagcctgc aaagcttgagaactcggccgtgtatctctgtgccagcagt SEQ ID NO: 572 TRBV11-2*03-5′ gaagctggagttgcccagtctcccagatataagattatagagaaaaggcagagtgtggct ttttggtgcaatcctatatctggccatgctaccctttact SEQ ID NO: 573 TRBV11-2*03-3′ ggatcgattttctgcagagaggctcaaaggagtagactccactctcaagatccaacctgc aaagcttgaggactcggccgtgtatctctgtgccagcagc SEQ ID NO: 574 TRBV11-3*01-5′ gaagctggagtggttcagtctcccagatataagattatagagaaaaaacagcctgtggct ttttggtgcaatcctatttctggccacaataccctttact SEQ ID NO: 575 TRBV11-3*01-3′ gattttctgcagagaggctcaaaggagtagactccactctcaagatccagcctgcagagc ttggggactcggccgtgtatctctgtgccagcagcttaga SEQ ID NO: 576 TRBV11-3*02-5′ gaagctggagtggttcagtctcccagatataagattatagagaaaaagcagcctgtggct ttttggtgcaatcctatttctggccacaataccctttact SEQ ID NO: 577 TRBV11-3*02-3′ ggatcgattttctgcagagaggctcaaaggagtagactccactctcaagatccagcctgc agagcttggggactcggccgtgtatctctgtgccagcagc SEQ ID NO: 578 TRBV11-3*03-5′ ggtctcccagatataagattatagagaagaaacagcctgtggctttttggtgcaatccaa tttctggccacaataccctttactggtacctgcagaactt SEQ ID NO: 579 TRBV11-3*03-3′ ggatcgattttctgcagagaggctcaaaggagtagactccactctcaagatccagccagc agagcttggggactcggccatgtatctctgtgccagcagc SEQ ID NO: 580 TRBV12-1*01-5′ gatgctggtgttatccagtcacccaggcacaaagtgacagagatgggacaatcagtaact ctgagatgcgaaccaatttcaggccacaatgatcttctct SEQ ID NO: 581 TRBV12-1*01-3′ gattctcagcacagatgcctgatgtatcattctccactctgaggatccagcccatggaac ccagggacttgggcctatatttctgtgccagcagctttgc SEQ ID NO: 582 TRBV12-2*01-5′ gatgctggcattatccagtcacccaagcatgaggtgacagaaatgggacaaacagtgact ctgagatgtgagccaatttttggccacaatttccttttct SEQ ID NO: 583 TRBV12-2*01-3′ gattctcagctgagaggcctgatggatcattctctactctgaagatccagcctgcagagc agggggactcggccgtgtatgtctgtgcaagtcgcttagc SEQ ID NO: 584 TRBV12-3*01-5′ gatgctggagttatccagtcaccccgccatgaggtgacagagatgggacaagaagtgact ctgagatgtaaaccaatttcaggccacaactcccttttct SEQ ID NO: 585 TRBV12-3*01-3′ gattctcagctaagatgcctaatgcatcattctccactctgaagatccagccctcagaac ccagggactcagctgtgtacttctgtgccagcagtttagc SEQ ID NO: 586 TRBV12-4*01-5′ gatgctggagttatccagtcaccccggcacgaggtgacagagatgggacaagaagtgact ctgagatgtaaaccaatttcaggacacgactaccttttct SEQ ID NO: 587 TRBV12-4*01-3′ gattctcagctaagatgcctaatgcatcattctccactctgaagatccagccctcagaac ccagggactcagctgtgtacttctgtgccagcagtttagc SEQ ID NO: 588 TRBV12-4*02-5′ gatgctggagttatccagtcaccccggcacgaggtgacagagatgggacaagaagtgact ctgagatgtaaaccaatttcaggacatgactaccttttct SEQ ID NO: 589 TRBV12-4*02-3′ tcgattctcagctaagatgcctaatgcatcattctccactctgaggatccagccctcaga acccagggactcagctgtgtacttctgtgccagcagttta SEQ ID NO: 590 TRBV12-5*01-5′ gatgctagagtcacccagacaccaaggcacaaggtgacagagatgggacaagaagtaaca atgagatgtcagccaattttaggccacaatactgttttct SEQ ID NO: 591 TRBV12-5*01-3′ gattctcagcagagatgcctgatgcaactttagccactctgaagatccagccctcagaac ccagggactcagctgtgtatttttgtgctagtggtttggt SEQ ID NO: 592 TRBV13*01-5′ gctgctggagtcatccagtccccaagacatctgatcaaagaaaagagggaaacagccact ctgaaatgctatcctatccctagacacgacactgtctact SEQ ID NO: 593 TRBV13*01-3′ gattctcagctcaacagttcagtgactatcattctgaactgaacatgagctccttggagc tgggggactcagccctgtacttctgtgccagcagcttagg SEQ ID NO: 594 TRBV13*02-5′ gctgctggagtcatccagtccccaagacatctgatcagagaaaagagggaaacagccact ctgaaatgctatcctatccctagacacgacactgtctact SEQ ID NO: 595 TRBV13*02-3′ tgatcgattctcagctcaacagttcagtgactatcattctgaactgaacatgagctcctt ggagctgggggactcagccctgtacttctgtgccagcagc SEQ ID NO: 596 TRBV14*01-5′ gaagctggagttactcagttccccagccacagcgtaatagagaagggccagactgtgact ctgagatgtgacccaatttctggacatgataatctttatt SEQ ID NO: 597 TRBV14*01-3′ gattcttagctgaaaggactggagggacgtattctactctgaaggtgcagcctgcagaac tggaggattctggagtttatttctgtgccagcagccaaga SEQ ID NO: 598 TRBV14*02-5′ gaagctggagttactcagttccccagccacagcgtaatagagaagggccagactgtgact ctgagatgtgacccaatttctggacatgataatctttatt SEQ ID NO: 599 TRBV14*02-3′ caatcgattcttagctgaaaggactggagggacgtattctactctgaaggtgcagcctgc agaactggaggattctggagtttatttctgtgccagcagc SEQ ID NO: 600 TRBV15*01-5′ gatgccatggtcatccagaacccaagataccaggttacccagtttggaaagccagtgacc ctgagttgttctcagactttgaaccataacgtcatgtact SEQ ID NO: 601 TRBV15*01-3′ acttccaatccaggaggccgaacacttctttctgctttcttgacatccgctcaccaggcc tgggggacacagccatgtacctgtgtgccaccagcagaga SEQ ID NO: 602 TRBV15*02-5′ gatgccatggtcatccagaacccaagataccaggttacccagtttggaaagccagtgacc ctgagttgttctcagactttgaaccataacgtcatgtact SEQ ID NO: 603 TRBV15*02-3′ tgataacttccaatccaggaggccgaacacttctttctgctttcttgacatccgctcacc aggcctgggggacgcagccatgtacctgtgtgccaccagc SEQ ID NO: 604 TRBV15*03-5′ gatgccatggtcatccagaacccaagataccgggttacccagtttggaaagccagtgacc ctgagttgttctcagactttgaaccataacgtcatgtact SEQ ID NO: 605 TRBV15*03-3′ tgataacttccaatccaggaggccgaacacttctttctgctttctagacatccgctcacc aggcctgggggacgcagccatgtaccagtgtgccaccagc SEQ ID NO: 606 TRBV16*01-5′ ggtgaagaagtcgcccagactccaaaacatcttgtcagaggggaaggacagaaagcaaaa ttatattgtgccccaataaaaggacacagttatgtttttt SEQ ID NO: 607 TRBV16*01-3′ gattttcagctaagtgcctcccaaattcaccctgtagccttgagatccaggctacgaagc ttgaggattcagcagtgtatttttgtgccagcagccaatc SEQ ID NO: 608 TRBV16*02-5′ ggtgaagaagtcgcccagactccaaaacatcttgtcagaggggaaggacagaaagcaaaa ttatattgtgccccaataaaaggacacagttaggtttttt SEQ ID NO: 609 TRBV16*02-3′ gattttcagctaagtgcctcccaaattcaccctgtagccttgagatccaggctacgaagc ttgaggattcagcagtgtatttttgtgccagcagccaatc SEQ ID NO: 610 TRBV16*03-5′ ggtgaagaagtcgcccagactccaaaacatcttgtcagaggggaaggacagaaagcaaaa ttatattgtgccccaataaaaggacacagttatgtttttt SEQ ID NO: 611 TRBV16*03-3′ ggaaagattttcagctaagtgcctcccaaattcaccctgtagccttgagatccaggctac gaagcttgaggattcagcagtgtatttttgtgccagcagc SEQ ID NO: 612 TRBV17*01-5′ gagcctggagtcagccagacccccagacacaaggtcaccaacatgggacaggaggtgatt ctgaggtgcgatccatcttctggtcacatgtttgttcact SEQ ID NO: 613 TRBV17*01-3′ aacgattcacagctgaaagacctaacggaacgtcttccacgctgaagatccatcccgcag agccgagggactcagccgtgtatctctacagtagcggtgg SEQ ID NO: 614 TRBV18*01-5′ aatgccggcgtcatgcagaacccaagacacctggtcaggaggaggggacaggaggcaaga ctgagatgcagcccaatgaaaggacacagtcatgtttact SEQ ID NO: 615 TRBV18*01-3′ gattttctgctgaatttcccaaagagggccccagcatcctgaggatccagcaggtagtgc gaggagattcggcagcttatttctgtgccagctcaccacc SEQ ID NO: 616 TRBV19*01-5′ gatggtggaatcactcagtccccaaagtacctgttcagaaaggaaggacagaatgtgacc ctgagttgtgaacagaatttgaaccacgatgccatgtact SEQ ID NO: 617 TRBV19*01-3′ ggtacagcgtctctcgggagaagaaggaatcctttcctctcactgtgacatcggcccaaa agaacccgacagctttctatctctgtgccagtagtataga SEQ ID NO: 618 TRBV19*02-5′ gatggtggaatcactcagtccccaaagtacctgttcagaaaggaaggacagaatgtgacc ctgagttgtgaacagaatttgaaccacgatgccatgtact SEQ ID NO: 619 TRBV19*02-3′ ggtacagcgtctctcgggagaagaaggaatcctttcctctcactgtgacatcggcccaaa agaacccgacagctttctatctctgtgccagtagtataga SEQ ID NO: 620 TRBV19*03-5′ gatggtggaatcactcagtccccaaagtacctgttcagaaaggaaggacagaatgtgacc ctgagttgtgaacagaatttgaaccacgatgccatgtact SEQ ID NO: 621 TRBV19*03-3′ tgaagggtacagcgtctctcgggagaagaaggaatcctttcctctcactgtgacatcggc ccaaaagaacccgacagctttctatctctgtgccagtagc SEQ ID NO: 622 TRBV2*01-5′ gaacctgaagtcacccagactcccagccatcaggtcacacagatgggacaggaagtgatc ttgcgctgtgtccccatctctaatcacttatacttctatt SEQ ID NO: 623 TRBV2*01-3′ aattctcagttgaaaggcctgatggatcaaatttcactctgaagatccggtccacaaagc tggaggactcagccatgtacttctgtgccagcagtgaagc SEQ ID NO: 624 TRBV2*02-5′ gaacctgaagtcacccagactcccagccatcaggtcacacagatgggacaggaagtgatc ttgcactgtgtccccatctctaatcacttatacttctatt SEQ ID NO: 625 TRBV2*02-3′ tgatcaattctcagttgaaaggcctgatggatcaaatttcactctgaagatccggtccac aaagctggaggactcagccatgtacttctgtgccagcagt SEQ ID NO: 626 TRBV2*03-5′ gaacctgaagtcacccagactcccagccatcaggtcacacagatgggacaggaagtgatc ttgcgctgtgtccccatctctaatcacttatacttctatt SEQ ID NO: 627 TRBV2*03-3′ tcaattctcagttgagaggcctgatggatcaaatttcactctgaagatccggtccacaaa gctggaggactcagccatgtacttctgtgccagcagtgaa SEQ ID NO: 628 TRBV20-1*01-5′ ggtgctgtcgtctctcaacatccgagctgggttatctgtaagagtggaacctctgtgaag atcgagtgccgttccctggactttcaggccacaactatgt SEQ ID NO: 629 TRBV20-1*01-3′ acaagtttctcatcaaccatgcaagcctgaccttgtccactctgacagtgaccagtgccc atcctgaagacagcagcttctacatctgcagtgctagaga SEQ ID NO: 630 TRBV20-1*02-5′ ggtgctgtcgtctctcaacatccgagcagggttatctgtaagagtggaacctctgtgaag atcgagtgccgttccctggactttcaggccacaactatgt SEQ ID NO: 631 TRBV20-1*02-3′ gaaggacaagtttctcatcaaccatgcaagcctgaccttgtccactctgacagtgaccag tgcccatcctgaagacagcagcttctacatctgcagtgct SEQ ID NO: 632 TRBV20-1*03-5′ ggtgctgtcgtctctcaacatccgagctgggttatctgtaagagtggaacctctgtgaag atcgagtgccgttccctggactttcaggccacaactatgt SEQ ID NO: 633 TRBV20-1*03-3′ gaaggacaagtttctcatcaaccatgcaagcctgaccttgtccactctgacagtgaccag tgcccatcctgaagacagcagcttctacatctgcagtgct SEQ ID NO: 634 TRBV20-1*04-5′ ggtgctgtcgtctctcaacatccgagcagggttatctgtaagagtggaacctctgtgaag atcgagtgccgttccttggactttcaggccacaactatgt SEQ ID NO: 635 TRBV20-1*04-3′ ggacaagtttctcatcaaccatgcaagcctgaccttgtccactctgacagtgaccagtgc ccatcctgaagacagcagcttctacatctgcagtgctagt SEQ ID NO: 636 TRBV20-1*05-5′ ggtgctgtcgtctctcaacatccgagcagggttatctgtaagagtggaacctctgtgaag atcgagtgccgttccctggactttcaggccacaactatgt SEQ ID NO: 637 TRBV20-1*05-3′ ggacaagtttctcatcaaccatgcaagcctgaccttgtccactctgacagtgaccagtgc ccatcctgaagacagcagcttctacatctgcagtgctaga SEQ ID NO: 638 TRBV20-1*06-5′ ggtgctgtcgtctctcaacatccgagtagggttatctgtaagagtggaacctctgtgaag atcgagtgccgttccctggactttcaggccacaactatgt SEQ ID NO: 639 TRBV20-1*06-3′ gaaggacaagtttctcatcaaccatgcaagcctgaccttgtccactctgacagtgaccag tgcccatcctgaagacagcagcttctacatctgcagtgct SEQ ID NO: 640 TRBV20-1*07-5′ ggtgctgtcgtctctcaacatccgagcagggttatctgtaagagtggaacctctgtgaag atcgagtgccgttccctggactttcaggccacaactatgt SEQ ID NO: 641 TRBV20-1*07-3′ ggacaagtttctcatcaaccatgcaagcctgaccttgtccactctgacagtgaccagtgc ccatcctgaagacagcagcttctacatctgcagtgctaga SEQ ID NO: 642 TRBV20/OR9-2*01-5′ agtgctgtcgtctctcaacatccgagcagggttatctgtaagagtggaacctctgtgaac atcgagtgccgttccctggactttcaggccacaactatgt SEQ ID NO: 643 TRBV20/OR9-2*01-3′ acaagtttcccatcaaccatccaaacctgaccttctccgctctgacagtgaccagtgccc atcctgaagacagcagcttctacatctgcagtgctagaga SEQ ID NO: 644 TRBV20/OR9-2*02-5′ ggtgctgtcgtctctcaacatccgagcagggttatctgtaagagtggaacctctgtgaac atcgagtgccgttccctggactttcaggccacaactatgt SEQ ID NO: 645 TRBV20/OR9-2*02-3′ gaaggacaagtttcccatcaaccatccaaacctgaccttctccgctctgacagtgacctg tgcccatcctgaagacagcagcttctacatctgcagtgct SEQ ID NO: 646 TRBV20/OR9-2*03-5′ agtgctgtcgtctctcaacatccgagcagggttatctgtaagagtggaacctctgtgaac atcgagtgccgttccctggactttcaggccacaactatgt SEQ ID NO: 647 TRBV20/OR9-2*03-3′ acaagtttcccatcaaccatccaaacctgaccttctccgctctgacagtgaccagtgccc atcctgaagacagcagcttctacatctgcagtgctagaga SEQ ID NO: 648 TRBV21-1*01-5′ gacaccaaggtcacccagagacctagacttctggtcaaagcaagtgaacagaaagcaaag atggattgtgttcctataaaagcacatagttatgtttact SEQ ID NO: 649 TRBV21-1*01-3′ gatttttagcccaatgctccaaaaactcatcctgtaccttggagatccagtccacggagt caggggacacagcactgtatttctgtgccagcagcaaagc SEQ ID NO: 650 TRBV21/OR9-2*01-5′ gacaccaaggtcacccagagacctagatttctggtcaaagcaaatgaacagaaagcaaag atggactgtgttcctataaaaagacatagttatgtttact SEQ ID NO: 651 TRBV21/OR9-2*01-3′ gattttcagcccaatgcccccaaaactcaccctgtaccttggagatccagtccacggagt caggagacacagcacggtatttctgtgccaacagcaaagc SEQ ID NO: 652 TRBV22-1*01-5′ gatgctgacatctatcagatgccattccagctcactggggctggatgggatgtgactctg gagtggaaacggaatttgagacacaatgacatgtactgct SEQ ID NO: 653 TRBV22-1*01-3′ aggctacgtgtctgccaagaggagaaggggctatttcttctcagggtgaagttggcccac accagccaaacagctttgtacttctgtcctgggagcgcac SEQ ID NO: 654 TRBV22/OR9-2*01-5′ gatgctgacatctatcagacgccattccagctcactggggctggatgggatgtgaccctg gagtagaaacaatttgagacacaatgacatgtactggtac SEQ ID NO: 655 TRBV22/OR9-2*01-3′ ggctacggtgtctcccgagaggagaaggggctgtttcttctcatggtgaagctggcccac accagccaaacagctctgtacttctgtcctgggagtgcac SEQ ID NO: 656 TRBV23-1*01-5′ catgccaaagtcacacagactccaggacatttggtcaaaggaaaaggacagaaaacaaag atggattgtacccccgaaaaaggacatacttttgtttatt SEQ ID NO: 657 TRBV23-1*01-3′ gattctcatctcaatgccccaagaacgcaccctgcagcctggcaatcctgtcctcagaac cgggagacacggcactgtatctctgcgccagcagtcaatc SEQ ID NO: 658 TRBV23/OR9-2*01-5′ catgccaaagtcacacagactccaggatatttggtcaaaggaaaaggaaggaaaacaaag atgtattgtacccccaaaaacggacatacttttgtttgtt SEQ ID NO: 659 TRBV23/OR9-2*01-3′ gatgcacaagaagcgattctcatctcaatgccccaagaacccaccctgcagcctggcaat cctgtcctcggaaccgggagacaccgcactgtatctctgt SEQ ID NO: 660 TRBV23/OR9-2*02-5′ catgccaaagtcacacagactccaggatatttggtcaaaggaaaaggaaggaaaacaaag atgtattgtacccccaaaaacggacatacttttgtttctt SEQ ID NO: 661 TRBV23/OR9-2*02-3′ gtttttgatttcctttcagaatgaacaagttcttcaagaaatggagatgcacaagaagcg attctcatctcaatgccccaagaacgcaccctgcagcctg SEQ ID NO: 662 TRBV24-1*01-5′ gatgctgatgttacccagaccccaaggaataggatcacaaagacaggaaagaggattatg ctggaatgttctcagactaagggtcatgatagaatgtact SEQ ID NO: 663 TRBV24-1*01-3′ atacagtgtctctcgacaggcacaggctaaattctccctgtccctagagtctgccatccc caaccagacagctctttacttctgtgccaccagtgatttg SEQ ID NO: 664 TRBV24/OR9-2*01-5′ gatgctgatgttacccagaccccaaggaataggatcacaaagacaggaaagaggattatg ctggaatgttctcagactaagggtcatgatagaatgtact SEQ ID NO: 665 TRBV24/OR9-2*01-3′ atacagtgtctctcgacaggcacaggctaaattctccctgtccctagagtctgccatccc caaccagacagctctttacttctgtgccaccagtgatttg SEQ ID NO: 666 TRBV24/OR9-2*02-5′ gatgctgatgttatccagaccccaaggaataggatcacaaagacaggaaagaggattatg ctggcatgttctcagactaagggtcatgatggaatgtact SEQ ID NO: 667 TRBV24/OR9-2*02-3′ cagttgatctattgctcctttgatgtcaaaatatataaacaaaagagagatctctgatgg atacagtgtctcttgacaggaacaggctaaattctccctg SEQ ID NO: 668 TRBV24/OR9-2*03-5′ gatgctgatgttatccagaccccaaggaataggatcacaaagacaggaaagaggattatg ctggaatgttctcagactaagggtcatgatggaatgtact SEQ ID NO: 669 TRBV24/OR9-2*03-3′ agtgtctcttgacaggaacaggctaaattctccctgtccctagagcctgccacccccaac cagacagcttctaggttacttcagtgccaccagtgatttc SEQ ID NO: 670 TRBV25-1*01-5′ gaagctgacatctaccagaccccaagataccttgttatagggacaggaaagaagatcact ctggaatgttctcaaaccatgggccatgacaaaatgtact SEQ ID NO: 671 TRBV25-1*01-3′ agtcaacagtctccagaataaggacggagcattttcccctgaccctggagtctgccaggc cctcacatacctctcagtacctctgtgccagcagtgaata SEQ ID NO: 672 TRBV25/OR9-2*01-5′ gaagctgaaatctaccagaccccaagacaccgtgttataggggcaggaaagaagatcact ctggaatgttctcaaaccatgggccatgacaaaatgtact SEQ ID NO: 673 TRBV25/OR9-2*01-3′ agtcaacagtctccagaataaggatagagcgttttcccctgaccctggagtctgccagcc cctcacatacctctcagtacctctgtgccagcagtgaata SEQ ID NO: 674 TRBV25/OR9-2*02-5′ gaagctgaaatctaccagaccccaagacaccgtgttataggggcaggaaagaagatcact ctggaatgttctcaaaccatgggccatgacaaaatgtact SEQ ID NO: 675 TRBV25/OR9-2*02-3′ gagttaattccacagagaagggagatctttgctctgagtcaacagtctccagaataagga tagagcgttttcccctgaccctggagtctgccagcccctc SEQ ID NO: 676 TRBV26-1*01-5′ gatgctgtagttacacaattcccaagacacagaatcattgggacaggaaaggaattcatt ctacagtgttcccagaatatgaatcatgttacaatgtact SEQ ID NO: 677 TRBV26-1*01-3′ ggtatcatgtttcttgaaatactatagcatcttttcccctgaccctgaagtctgccagca ccaaccagacatctgtgtatctctatgccagcagttcatc SEQ ID NO: 678 TRBV26/OR9-2*01-5′ gatgctgtagttacacaattctcaagacacagaatcattgggacaggaaaggaattcatt ctactgtgtccccagaatatgaatcatgttgcaatgtact SEQ ID NO: 679 TRBV26/OR9-2*01-3′ ggtatcatgtttcttgaaatactatagcatcttttctcctgaccctgaagtctgctagca ccaaccagacatgtgtgtatctctgcgccagcagttcatc SEQ ID NO: 680 TRBV26/OR9-2*02-5′ gatgctgtagttacacaattcccaagacacagaatcattgggacaggaaaggaattcatt ctactgtgtccccagaatatgaatcatgttgcaatgtact SEQ ID NO: 681 TRBV26/OR9-2*02-3′ ggtatcatgtttcttgaaatactatagcatcttttctcctgaccctgaagtctgctagca ccaaccagacatgtgtgtatctctgcgccagcagttcatc SEQ ID NO: 682 TRBV27*01-5′ gaagcccaagtgacccagaacccaagatacctcatcacagtgactggaaagaagttaaca gtgacttgttctcagaatatgaaccatgagtatatgtcct SEQ ID NO: 683 TRBV27*01-3′ ggtacaaagtctctcgaaaagagaagaggaatttccccctgatcctggagtcgcccagcc ccaaccagacctctctgtacttctgtgccagcagtttatc SEQ ID NO: 684 TRBV28*01-5′ gatgtgaaagtaacccagagctcgagatatctagtcaaaaggacgggagagaaagttttt ctggaatgtgtccaggatatggaccatgaaaatatgttct SEQ ID NO: 685 TRBV28*01-3′ ggtacagtgtctctagagagaagaaggagcgcttctccctgattctggagtccgccagca ccaaccagacatctatgtacctctgtgccagcagtttatg SEQ ID NO: 686 TRBV29-1*01-5′ agtgctgtcatctctcaaaagccaagcagggatatctgtcaacgtggaacctccctgacg atccagtgtcaagtcgatagccaagtcaccatgatgttct SEQ ID NO: 687 TRBV29-1*01-3′ acaagtttcccatcagccgcccaaacctaacattctcaactctgactgtgagcaacatga gccctgaagacagcagcatatatctctgcagcgttgaaga SEQ ID NO: 688 TRBV29-1*02-5′ agtgctgtcatctctcaaaagccaagcagggatatctgtcaacgtggaacctccctgacg atccagtgtcaagtcgatagccaagtcaccatgatgttc SEQ ID NO: 689 TRBV29-1*02-3′ tgacaagtttcccatcagccgcccaaacctaacattctcaagtctgactgtgagcaacat gagccctgaagacagcagcatatatctctgcagcgttgaa SEQ ID NO: 690 TRBV29-1*03-5′ acgatccagtgtcaagtcgatagccaagtcaccatgatattctggtaccgtcagcaacct ggacagagcctgacactgatcgcaactgcaaatcagggct SEQ ID NO: 691 TRBV29-1*03-3′ tgacaagtttcccatcagccgcccaaacctaacattctcaactctgactgtgagcaacat gagccctgaagacagcagcatatatctctgcagcgcgggc SEQ ID NO: 692 TRBV29/OR9-2*01-5′ agtgctgtcatctctcaaaagccaagcagggatatctgtcaacgtggaacctccatgatg atccagtgtcaagtcgacagccaagtcaccatgatgttct SEQ ID NO: 693 TRBV29/OR9-2*01-3′ acaagtttcccatcagccgcccaaacctaacattctcaactctgactgtgagcaacagga gacctgaagacagcagcatatacctctgcagcgttgaaga SEQ ID NO: 694 TRBV29/OR9-2*02-5′ agtgctgtcatctctcaaaagccaagcagggatatctgtcaacgtggaacctccatgatg atccagtgtcaagtcgacagccaagtcaccatgatgttct SEQ ID NO: 695 TRBV29/OR9-2*02-3′ acaagtttcccatcagccgcccaaacctaacattctcaactctgactgtgagcaacagga gacctgaagacagcagcatatacctctgcagcgttgaaga SEQ ID NO: 696 TRBV3-1*01-5′ gacacagctgtttcccagactccaaaatacctggtcacacagatgggaaacgacaagtcc attaaatgtgaacaaaatctgggccatgatactatgtatt SEQ ID NO: 697 TRBV3-1*01-3′ gcttctcacctaaatctccagacaaagctcacttaaatcttcacatcaattccctggagc ttggtgactctgctgtgtatttctgtgccagcagccaaga SEQ ID NO: 698 TRBV3-1*02-5′ gacacagctgtttcccagactccaaaatacctggtcacacagatgggaaacgacaagtcc attaaatgtgaacaaaatctgggccatgatactatgtatt SEQ ID NO: 699 TRBV3-1*02-3′ tccaaatcgattctcacctaaatctccagacaaagctaaattaaatcttcacatcaattc cctggagcttggtgactctgctgtgtatttctgtgccagc SEQ ID NO: 700 TRBV3-2*01-5′ gacacagccgtttcccagactccaaaatacctggtcacacagatgggaaaaaaggagtct cttaaatgagaacaaaatctgggccataatgctatgtatt SEQ ID NO: 701 TRBV3-2*01-3′ gcttctcacctgactctccagacaaagctcatttaaatcttcacatcaattccctggagc ttggtgactctgctgtgtatttctgtgccagcagccaaga SEQ ID NO: 702 TRBV3-2*02-5′ gacacagccgtttcccagactccaaaatacctggtcacacagatgggaaaaaaggagtct cttaaatgagaacaaaatctgggccataatgctatgtatt SEQ ID NO: 703 TRBV3-2*02-3′ gcttctcacctgactctccagacaaagttcatttaaatcttcacatcaattccctggagc ttggtgactctgctgtgtatttctgtgccagcagccaaga SEQ ID NO: 704 TRBV3-2*03-5′ gacacagccgtttcccagactccaaaatacctggtcacacagacgggaaaaaaggagtct cttaaatgagaacaaaatctgggccataatgctatgtatt SEQ ID NO: 705 TRBV3-2*03-3′ tcgcttctcacctgactctccagacaaagttcatttaaatcttcacatcaattccctgga gcttggtgactctgctgtgtatttctgtgccagcagccaa SEQ ID NO: 706 TRBV30*01-5′ tctcagactattcatcaatggccagcgaccctggtgcagcctgtgggcagcccgctctct ctggagtgcactgtggagggaacatcaaaccccaacctat SEQ ID NO: 707 TRBV30*01-3′ agaatctctcagcctccagaccccaggaccggcagttcatcctgagttctaagaagctcc ttctcagtgactctggcttctatctctgtgcctggagtgt SEQ ID NO: 708 TRBV30*02-5′ tctcagactattcatcaatggccagcgaccctggtgcagcctgtgggcagcccgctctct ctggagtgcactgtggagggaacatcaaaccccaacctat SEQ ID NO: 709 TRBV30*02-3′ agaatctctcagcctccagaccccaggaccggcagttcatcctgagttctaagaagctcc tcctcagtgactctggcttctatctctgtgcctggagtgt SEQ ID NO: 710 TRBV30*04-5′ actattcatcaatggccagcgaccctggtgcagcctgtgggcagcccgctctctctggag tgcactgtggagggaacatcaaaccccaacctatactggt SEQ ID NO: 711 TRBV30*04-3′ ccagaatctctcagcctccagaccccaggaccggcagttcattctgagttctaagaagct cctcctcagtgactctggcttctatctctgtgcctggagt SEQ ID NO: 712 TRBV30*05-5′ tctcagactattcatcaatggccagcgaccctggtgcagcctgtgggcagcccgctctcc ctggagtgcactgtggagggaacatcaaaccccaacctat SEQ ID NO: 713 TRBV30*05-3′ ccagaatctctcagcctccagaccccaggaccggcagttcatcctgagttctaagaagct ccttctcagtgactctggcttctatctctgtgcctgggga SEQ ID NO: 714 TRBV4-1*01-5′ gacactgaagttacccagacaccaaaacacctggtcatgggaatgacaaataagaagtct ttgaaatgtgaacaacatatggggcacagggctatgtatt SEQ ID NO: 715 TRBV4-1*01-3′ gcttctcacctgaatgccccaacagctctctcttaaaccttcacctacacgccctgcagc cagaagactcagccctgtatctctgcgccagcagccaaga SEQ ID NO: 716 TRBV4-1*02-5′ cacctggtcatgggaatgacaaataagaagtctttgaaatgtgaacaacatatggggcac agggcaatgtattggtacaagcagaaagctaagaagccac SEQ ID NO: 717 TRBV4-1*02-3′ tcgcttctcacctgaatgccccaacagctctctcttaaaccttcacctacacgccctgca gccagaagactcagccctgtatctctgcgccagcagccaa SEQ ID NO: 718 TRBV4-2*01-5′ gaaacgggagttacgcagacaccaagacacctggtcatgggaatgacaaataagaagtct ttgaaatgtgaacaacatctggggcataacgctatgtatt SEQ ID NO: 719 TRBV4-2*01-3′ gcttctcacctgaatgccccaacagctctcacttattccttcacctacacaccctgcagc cagaagactcggccctgtatctctgtgccagcagccaaga SEQ ID NO: 720 TRBV4-2*02-5′ gaaacgggagttacgcagacaccaagacacctggtcatgggaatgacaaataagaagtct ttgaaatgtgaacaacatctggggcataacgctatgtatt SEQ ID NO: 721 TRBV4-2*02-3′ aagtcgcttctcacctgaatgccccaacagctctcacttatgccttcacctacacaccct gcagccagaagactcggccctgtatctctgtgccagcacc SEQ ID NO: 722 TRBV4-3*01-5′ gaaacgggagttacgcagacaccaagacacctggtcatgggaatgacaaataagaagtct ttgaaatgtgaacaacatctgggtcataacgctatgtatt SEQ ID NO: 723 TRBV4-3*01-3′ gcttctcacctgaatgccccaacagctctcacttattccttcacctacacaccctgcagc cagaagactcggccctgtatctctgcgccagcagccaaga SEQ ID NO: 724 TRBV4-3*02-5′ gaaacgggagttacgcagacaccaagacacctggtcatgggaatgacaaataagaagtct ttgaaatgtgaacaacatctgggtcataacgctatgtatt SEQ ID NO: 725 TRBV4-3*02-3′ aagtcgcttctcacctgaatgccccaacagctctcacttatcccttcacctacacaccct gcagccagaagactcggccctgtatctctgcgccagcagc SEQ ID NO: 726 TRBV4-3*03-5′ gaaacgggagttacgcagacaccaagacacctggtcatgggaatgacaaataagaagtct ttgaaatgtgaacaacatctgggtcataacgctatgtatt SEQ ID NO: 727 TRBV4-3*03-3′ aagtcgcttctcacctgaatgccccaacagctctcacttattccttcacctacacaccct gcagccagaagactcggccctgtatctctgcgccagcagc SEQ ID NO: 728 TRBV4-3*04-5′ aagaagtctttgaaatgtgaacaacatctggggcataacgctatgtattggtacaagcaa agtgctaagaagccactggagctcatgtttgtctacagtc SEQ ID NO: 729 TRBV4-3*04-3′ aagtcgcttctcacctgaatgccccaacagctctcacttattccttcacctacacaccct gcagccagaagactcggccctgtatctctgcgccagcagc SEQ ID NO: 730 TRBV5-1*01-5′ aaggctggagtcactcaaactccaagatatctgatcaaaacgagaggacagcaagtgaca ctgagctgctcccctatctctgggcataggagtgtatcct SEQ ID NO: 731 TRBV5-1*01-3′ cgattctcagggcgccagttctctaactctcgctctgagatgaatgtgagcaccttggag ctgggggactcggccctttatctttgcgccagcagcttgg SEQ ID NO: 732 TRBV5-1*02-5′ agggctggggtcactcaaactccaagacatctgatcaaaacgagaggacagcaagtgaca ctgggctgctcccctatctctgggcataggagtgtatcct SEQ ID NO: 733 TRBV5-1*02-3′ tcgattctcagggcgccagttctctaactctcgctctgagatgaatgtgagcaccttgga gctgggggactcggccctttatctttgcgccagcgcttgc SEQ ID NO: 734 TRBV5-2*01-5′ gaggctggaatcacccaagctccaagacacctgatcaaaacaagagaccagcaagtgaca ctgagatgctcccctgcctctgggcataactgtgtgtcct SEQ ID NO: 735 TRBV5-2*01-3′ aacttgcctaattgattctcagctcaccacgtccataactattactgagtcaaacacgga gctaggggactcagccctgtatctctgtgccagcaacttg SEQ ID NO: 736 TRBV5-3*01-5′ gaggctggagtcacccaaagtcccacacacctgatcaaaacgagaggacagcaagtgact ctgagatgctctcctatctctgggcacagcagtgtgtcct SEQ ID NO: 737 TRBV5-3*01-3′ cgattctcagggcgccagttccatgactgttgctctgagatgaatgtgagtgccttggag ctgggggactcggccctgtatctctgtgccagaagcttgg SEQ ID NO: 738 TRBV5-3*02-5′ gaggctggagtcacccaaagtcccacacacctgatcaaaacgagaggacagcaagtgact ctgagatgctctcctatctctgggcacagcagtgtgtcct SEQ ID NO: 739 TRBV5-3*02-3′ cgattctcagggcgccagttccatgactattgctctgagatgaatgtgagtgccttggag ctgggggactcggccctgtatctctgtgccagaagcttgg SEQ ID NO: 740 TRBV5-4*01-5′ gagactggagtcacccaaagtcccacacacctgatcaaaacgagaggacagcaagtgact ctgagatgctcttctcagtctgggcacaacactgtgtcct SEQ ID NO: 741 TRBV5-4*01-3′ agattctcaggtctccagttccctaattatagctctgagctgaatgtgaacgccttggag ctggacgactcggccctgtatctctgtgccagcagcttgg SEQ ID NO: 742 TRBV5-4*02-5′ gagactggagtcacccaaagtcccacacacctgatcaaaacgagaggacagcaagtgact ctgagatgctcttctcagtctgggcacaacactgtgtcct SEQ ID NO: 743 TRBV5-4*02-3′ tcctagattctcaggtctccagttccctaattataactctgagctgaatgtgaacgcctt ggagctggacgactcggccctgtatctctgtgccagcagc SEQ ID NO: 744 TRBV5-4*03-5′ cagcaagtgacactgagatgctcttctcagtctgggcacaacactgtgtcctggtaccaa caggccctgggtcaggggccccagtttatctttcagtatt SEQ ID NO: 745 TRBV5-4*03-3′ tcctagattctcaggtctccagttccctaattatagctctgagctgaatgtgaacgcctt ggagctggacgactcggccctgtatctctgtgccagcagc SEQ ID NO: 746 TRBV5-4*04-5′ actgtgtcctggtaccaacaggccctgggtcaggggccccagtttatctttcagtattat agggaggaagagaatggcagaggaaactcccctcctagat SEQ ID NO: 747 TRBV5-4*04-3′ tcctagattctcaggtctccagttccctaattatagctctgagctgaatgtgaacgcctt ggagctggacgactcggccctgtatctctgtgccagcagc SEQ ID NO: 748 TRBV5-5*01-5′ gacgctggagtcacccaaagtcccacacacctgatcaaaacgagaggacagcaagtgact ctgagatgctctcctatctctgggcacaagagtgtgtcct SEQ ID NO: 749 TRBV5-5*01-3′ cgattctcagctcgccagttccctaactatagctctgagctgaatgtgaacgccttgttg ctgggggactcggccctgtatctctgtgccagcagcttgg SEQ ID NO: 750 TRBV5-5*02-5′ gacgctggagtcacccaaagtcccacacacctgatcaaaacgagaggacagcacgtgact ctgagatgctctcctatctctgggcacaagagtgtgtcct SEQ ID NO: 751 TRBV5-5*02-3′ tgatcgattctcagctcgccagttccctaactatagctctgagctgaatgtgaacgcctt gttgctgggggactcggccctgtatctctgtgccagcagc SEQ ID NO: 752 TRBV5-5*03-5′ gacgctggagtcacccaaagtcccacacacctgatcaaaacgagaggacagcaagtgact ctgagatgctctcctatctctgagcacaagagtgtgtcct SEQ ID NO: 753 TRBV5-5*03-3′ tgatcgattctcagctcgccagttccctaactatagctctgagctgaatgtgaacgcctt gttgctgggggactcggccctgtatctctgtgccagcagc SEQ ID NO: 754 TRBV5-6*01-5′ gacgctggagtcacccaaagtcccacacacctgatcaaaacgagaggacagcaagtgact ctgagatgctctcctaagtctgggcatgacactgtgtcct SEQ ID NO: 755 TRBV5-6*01-3′ cgattctcaggtcaccagttccctaactatagctctgagctgaatgtgaacgccttgttg ctgggggactcggccctctatctctgtgccagcagcttgg SEQ ID NO: 756 TRBV5-7*01-5′ gacgctggagtcacccaaagtcccacacacctgatcaaaacgagaggacagcacgtgact ctgagatgctctcctatctctgggcacaccagtgtgtcct SEQ ID NO: 757 TRBV5-7*01-3′ caattctcaggtcaccagttccctaactatagctctgagctgaatgtgaacgccttgttg ctaggggactcggccctctatctctgtgccagcagcttgg SEQ ID NO: 758 TRBV5-8*01-5′ gaggctggagtcacacaaagtcccacacacctgatcaaaacgagaggacagcaagcgact ctgagatgctctcctatctctgggcacaccagtgtgtact SEQ ID NO: 759 TRBV5-8*01-3′ agattttcaggtcgccagttccctaattatagctctgagctgaatgtgaacgccttggag ctggaggactcggccctgtatctctgtgccagcagcttgg SEQ ID NO: 760 TRBV5-8*02-5′ aggacagcaagcgactctgagatgctctcctatctctgggcacaccagtgtgtactggta ccaacaggccctgggtctgggcctccagctcctcctttgg SEQ ID NO: 761 TRBV5-8*02-3′ tcctagattttcaggtcgccagttccctaattatagctctgagctgaatgtgaacgcctt ggagctggaggactcggccctgtatctctgtgccagcagc SEQ ID NO: 762 TRBV6-1*01-5′ aatgctggtgtcactcagaccccaaaattccaggtcctgaagacaggacagagcatgaca ctgcagtgtgcccaggatatgaaccataactccatgtact SEQ ID NO: 763 TRBV6-1*01-3′ gctacaatgtctccagattaaacaaacgggagttctcgctcaggctggagtcggctgctc cctcccagacatctgtgtacttctgtgccagcagtgaagc SEQ ID NO: 764 TRBV6-2*01-5′ aatgctggtgtcactcagaccccaaaattccgggtcctgaagacaggacagagcatgaca ctgctgtgtgcccaggatatgaaccatgaatacatgtact SEQ ID NO: 765 TRBV6-2*01-3′ gctacaatgtctccagattaaaaaaacagaatttcctgctggggttggagtcggctgctc cctcccaaacatctgtgtacttctgtgccagcagttactc SEQ ID NO: 766 TRBV6-2*02-5′ aatgctggtgtcactcagaccccaaaattccgggtcctgaagacaggacagagcatgaca ctgctgtgtgcccaggatatgaaccatgaatacatgtact SEQ ID NO: 767 TRBV6-2*02-3′ tggctacaatgtctccagattaaaaaaacagaatttcctgctggggttggagtcggctgc tccctcccaaacatctgtgtacttctgtgccagcagccct SEQ ID NO: 768 TRBV6-3*01-5′ aatgctggtgtcactcagaccccaaaattccgggtcctgaagacaggacagagcatgaca ctgctgtgtgcccaggatatgaaccatgaatacatgtact SEQ ID NO: 769 TRBV6-3*01-3′ gctacaatgtctccagattaaaaaaacagaatttcctgctggggttggagtcggctgctc cctcccaaacatctgtgtacttctgtgccagcagttactc SEQ ID NO: 770 TRBV6-4*01-5′ attgctgggatcacccaggcaccaacatctcagatcctggcagcaggacggcgcatgaca ctgagatgtacccaggatatgagacataatgccatgtact SEQ ID NO: 771 TRBV6-4*01-3′ gttatagtgtctccagagcaaacacagatgatttccccctcacgttggcgtctgctgtac cctctcagacatctgtgtacttctgtgccagcagtgactc SEQ ID NO: 772 TRBV6-4*02-5′ actgctgggatcacccaggcaccaacatctcagatcctggcagcaggacggagcatgaca ctgagatgtacccaggatatgagacataatgccatgtact SEQ ID NO: 773 TRBV6-4*02-3′ gttatagtgtctccagagcaaacacagatgatttccccctcacgttggcgtctgctgtac cctctcagacatctgtgtacttctgtgccagcagtgactc SEQ ID NO: 774 TRBV6-5*01-5′ aatgctggtgtcactcagaccccaaaattccaggtcctgaagacaggacagagcatgaca ctgcagtgtgcccaggatatgaaccatgaatacatgtcct SEQ ID NO: 775 TRBV6-5*01-3′ gctacaatgtctccagatcaaccacagaggatttcccgctcaggctgctgtcggctgctc cctcccagacatctgtgtacttctgtgccagcagttactc SEQ ID NO: 776 TRBV6-6*01-5′ aatgctggtgtcactcagaccccaaaattccgcatcctgaagataggacagagcatgaca ctgcagtgtacccaggatatgaaccataactacatgtact SEQ ID NO: 777 TRBV6-6*01-3′ gctacaacgtctccagatcaaccacagaggatttcccgctcaggctggagttggctgctc cctcccagacatctgtgtacttctgtgccagcagttactc SEQ ID NO: 778 TRBV6-6*02-5′ aatgctggtgtcactcagaccccaaaattccgcatcctgaagataggacagagcatgaca ctgcagtgtgcccaggatatgaaccataactacatgtact SEQ ID NO: 779 TRBV6-6*02-3′ gaatggctacaacgtctccagatcaaccacagaggatttcccgctcaggctggagttggc tgctccctcccagacatctgtgtacttctgtgccagcagt SEQ ID NO: 780 TRBV6-6*03-5′ aatgctggtgtcactcagaccccaaaattccgcatcctgaagataggacagagcatgaca ctgcagtgtgcccaggatatgaaccataactacatgtact SEQ ID NO: 781 TRBV6-6*03-3′ gaatggctacaacgtctccagatcaaccacagaggatttcccgctcaggctggagttggc tgctccctcccagacatctgtgtacttctgtgccagcagt SEQ ID NO: 782 TRBV6-6*04-5′ aatgctggtgtcactcagaccccaaaattccgcatcctgaagataggacagagcatgaca ctgcagtgtacccaggatatgaaccatgaatacatgtact SEQ ID NO: 783 TRBV6-6*04-3′ tggctacaatgtctccagatcaaccacagaggatttcccgctcaggctggagttggctgc tccctcccagacatctgtgtacttctgtgccagcagtcga SEQ ID NO: 784 TRBV6-6*05-5′ aatgctggtgtcactcagaccccaaaattccgcatcctgaagataggacagagcatgaca ctgcagtgtgcccaggatatgaaccataactacatgtact SEQ ID NO: 785 TRBV6-6*05-3′ gaatggctacaacgtctccagatcaaccacagaggatttcccgctcaggctggagttggc tgctgcctcccagacatctgtgtacttctgtgccagcagc SEQ ID NO: 786 TRBV6-7*01-5′ aatgctggtgtcactcagaccccaaaattccacgtcctgaagacaggacagagcatgact ctgctgtgtgcccaggatatgaaccatgaatacatgtatc SEQ ID NO: 787 TRBV6-7*01-3′ gctacaatgtctccagatcaaacacagaggatttccccctcaagctggagtcagctgctc cctctcagacttctgtttacttctgtgccagcagttactc SEQ ID NO: 788 TRBV6-8*01-5′ aatgctggtgtcactcagaccccaaaattccacatcctgaagacaggacagagcatgaca ctgcagtgtgcccaggatatgaaccatggatacatgtcct SEQ ID NO: 789 TRBV6-8*01-3′ gctacaatgtctctagattaaacacagaggatttcccactcaggctggtgtcggctgctc cctcccagacatctgtgtacttgtgtgccagcagttactc SEQ ID NO: 790 TRBV6-9*01-5′ aatgctggtgtcactcagaccccaaaattccacatcctgaagacaggacagagcatgaca ctgcagtgtgcccaggatatgaaccatggatacttgtcct SEQ ID NO: 791 TRBV6-9*01-3′ gctacaatgtatccagatcaaacacagaggatttcccgctcaggctggagtcagctgctc cctcccagacatctgtatacttctgtgccagcagttattc SEQ ID NO: 792 TRBV7-1*01-5′ ggtgctggagtctcccagtccctgagacacaaggtagcaaagaagggaaaggatgtagct ctcagatatgatccaatttcaggtcataatgccctttatt SEQ ID NO: 793 TRBV7-1*01-3′ ggttctctgcacagaggtctgagggatccatctccactctgaagttccagcgcacacagc agggggacttggctgtgtatctctgtgccagcagctcagc SEQ ID NO: 794 TRBV7-2*01-5′ ggagctggagtctcccagtcccccagtaacaaggtcacagagaagggaaaggatgtagag ctcaggtgtgatccaatttcaggtcatactgccctttact SEQ ID NO: 795 TRBV7-2*01-3′ gcttctctgcagagaggactgggggatccgtctccactctgacgatccagcgcacacagc aggaggactcggccgtgtatctctgtgccagcagcttagc SEQ ID NO: 796 TRBV7-2*02-5′ ggagctggagtctcccagtcccccagtaacaaggtcacagagaagggaaaggatgtagag ctcaggtgtgatccaatttcaggtcatactgccctttact SEQ ID NO: 797 TRBV7-2*02-3′ gcttctctgcagagaggactggggaatccgtctccactctgacgatccagcgcacacagc aggaggactcggccgtgtatctctgtgccagcagcttagc SEQ ID NO: 798 TRBV7-2*03-5′ ggagctggagtctcccagtcccccagtaacaaggtcacagagaagggaaaggatgtagag ctcaggtgtgatccaatttcaggtcatactgccctttact SEQ ID NO: 799 TRBV7-2*03-3′ gcttctctgcagagaggactggggaatccgtctccactctgacgatccagcgcacacagc aggaggactcggccgtgtatctctgtaccagcagcttagc SEQ ID NO: 800 TRBV7-2*04-5′ ggagctggagtttcccagtcccccagtaacaaggtcacagagaagggaaaggatgtagag ctcaggtgtgatccaatttcaggtcatactgccctttact SEQ ID NO: 801 TRBV7-2*04-3′ tcgcttctctgcagagaggactgggggatccgtctccactctgacgatccagcgcacaca gcaggaggactcggccgtgtatctctgtgccagcagctta SEQ ID NO: 802 TRBV7-3*01-5′ ggtgctggagtctcccagacccccagtaacaaggtcacagagaagggaaaatatgtagag ctcaggtgtgatccaatttcaggtcatactgccctttact SEQ ID NO: 803 TRBV7-3*01-3′ ggttctttgcagtcaggcctgagggatccgtctctactctgaagatccagcgcacagagc ggggggactcagccgtgtatctctgtgccagcagcttaac SEQ ID NO: 804 TRBV7-3*02-5′ ggtgctggagtctcccagacccccagtaacaaggtcacagagaagggaaaagatgtagag ctcaggtgtgatccaatttcaggtcatactgccctttact SEQ ID NO: 805 TRBV7-3*02-3′ ggttctttgcagtcaggcctgagggatccgtctctactctgaagatccagcgcacagagc agggggactcagccgtgtatctccgtgccagcagcttaac SEQ ID NO: 806 TRBV7-3*03-5′ ggtgctggagtctcccagacccccagtaacaaggtcacagagaagggaaaagatgtagag ctcaggtgtgatccaatttcaggtcatactgccctttact SEQ ID NO: 807 TRBV7-3*03-3′ ggttctttgcagtcaggcctgagggatccgtctctactctgaagatccagcgcacagagc agggggactcagccgcgtatctccgtgccagcagcttaac SEQ ID NO: 808 TRBV7-3*04-5′ ggtgctggagtctcccagacccccagtaacaaggtcacagagaagggaaaatatgtagag ctcaggtgtgatccaatttcaggtcatactgccctttact SEQ ID NO: 809 TRBV7-3*04-3′ cgatcggttctttgcagtcaggcctgagggatccgtctctactctgaagatccagcgcac agagcggggggactctgccgtgtatctctgtgccagcagc SEQ ID NO: 810 TRBV7-3*05-5′ tgggagctcaggtgtgatccaatttcaggtcatactgccctttactggtaccgacaaagc ctggggcagggcccagagcttctaatttacttccaaggca SEQ ID NO: 811 TRBV7-3*05-3′ cgatcggttctttgcagtcaggcctgagggatccgtctctactctgaagatccagcgcac agagcggggggactcagccgtgtatctctgtgccagcagc SEQ ID NO: 812 TRBV7-4*01-5′ ggtgctggagtctcccagtccccaaggtacaaagtcgcaaagaggggacgggatgtagct ctcaggtgtgattcaatttcgggtcatgtaaccctttatt SEQ ID NO: 813 TRBV7-4*01-3′ ggttctctgcagagaggcctgagagatccgtctccactctgaagatccagcgcacagagc agggggactcagctgtgtatctctgtgccagcagcttagc SEQ ID NO: 814 TRBV7-4*02-5′ ggtgctggagtctcccagtccccaaggtacaaagtcgcaaagaggggacgggatgtagct ctcaggtgtgattcaatttcgggtcatgtaaccctttatt SEQ ID NO: 815 TRBV7-4*02-3′ aacgagacaaatcagggcggcccagtggtcggttctctgcagagaggcctgagagatcgt ctccactccgaagatccagcgcacagagcagggggactca SEQ ID NO: 816 TRBV7-5*01-5′ ggtgctggagtctcccagtccccaaggtacgaagtcacacagaggggacaggatgtagct cccaggtgtgatccaatttcgggtcaggtaaccctttatt SEQ ID NO: 817 TRBV7-5*01-3′ tcaattctccacagagaggtctgaggatctttctccacctgaagatccagcgcacagagc aagggcgactcggctgtgtatctctgtgccagaagcttag SEQ ID NO: 818 TRBV7-5*02-5′ ggtgctggagtctcccagtccccaaggtacgaagtcacacagaggggacaggatgtagct cccaggtgtgatccaatttcgggtcaggtaaccctttatt SEQ ID NO: 819 TRBV7-5*02-3′ caattctccacagagaggtctgaggatctttctccacctgaagatccagcgcacagagca agggcgactcggctgtgtatctctgtgtcagaagcttagc SEQ ID NO: 820 TRBV7-6*01-5′ ggtgctggagtctcccagtctcccaggtacaaagtcacaaagaggggacaggatgtagct ctcaggtgtgatccaatttcgggtcatgtatccctttatt SEQ ID NO: 821 TRBV7-6*01-3′ ggttctctgcagagaggcctgagggatccatctccactctgacgatccagcgcacagagc agcgggactcggccatgtatcgctgtgccagcagcttagc SEQ ID NO: 822 TRBV7-6*02-5′ ggtgctggagtctcccagtctcccaggtacaaagtcacaaagaggggacaggatgtagct ctcaggtgtgatccaatctcgggtcatgtatccctttatt SEQ ID NO: 823 TRBV7-6*02-3′ tgatcggttctctgcagagaggcctgagggatccatctccactctgacgatccagcgcac agagcagcgggactcggccatgtatcgctgtgccagcagc SEQ ID NO: 824 TRBV7-7*01-5′ ggtgctggagtctcccagtctcccaggtacaaagtcacaaagaggggacaggatgtaact ctcaggtgtgatccaatttcgagtcatgcaaccctttatt SEQ ID NO: 825 TRBV7-7*01-3′ ggttctctgcagagaggcctgagggatccatctccactctgacgattcagcgcacagagc agcgggactcagccatgtatcgctgtgccagcagcttagc SEQ ID NO: 826 TRBV7-7*02-5′ ggtgctggagtctcccagtctcccaggtacaaagtcacaaagaggggacaggatgtaact ctcaggtgtgatccaatttcgagtcatgtaaccctttatt SEQ ID NO: 827 TRBV7-7*02-3′ tgatcggttctctgcagagaggcctgagggatccatctccactctgacgattcagcgcac agagcagcgggactcagccatgtatcgctgtgccagcagc SEQ ID NO: 828 TRBV7-8*01-5′ ggtgctggagtctcccagtcccctaggtacaaagtcgcaaagagaggacaggatgtagct ctcaggtgtgatccaatttcgggtcatgtatccctttttt SEQ ID NO: 829 TRBV7-8*01-3′ gcttctttgcagaaaggcctgagggatccgtctccactctgaagatccagcgcacacagc aggaggactccgccgtgtatctctgtgccagcagcttagc SEQ ID NO: 830 TRBV7-8*02-5′ ggtgctggagtctcccagtcccctaggtacaaagtcgcaaagagaggacaggatgtagct ctcaggtgtgatccaatttcgggtcatgtatccctttttt SEQ ID NO: 831 TRBV7-8*02-3′ gcttctttgcagaaaggcctgagggatccgtctccactctgaagatccagcgcacacaga aggaggactccgccgtgtatctctgtgccagcagcttagc SEQ ID NO: 832 TRBV7-8*03-5′ ggtgctggagtctcccagtcccctaggtacaaagtcgcaaagagaggacaggatgtagct ctcaggtgtgatccaatttcgggtcatgtatccctttttt SEQ ID NO: 833 TRBV7-8*03-3′ tcgcttctttgcagaaaggcctgagggatccgtctccactctgaagatccagcgcacaca gcaggaggactccgccgtgtatctctgtgccagcagccga SEQ ID NO: 834 TRBV7-9*01-5′ gatactggagtctcccagaaccccagacacaagatcacaaagaggggacagaatgtaact ttcaggtgtgatccaatttctgaacacaaccgcctttatt SEQ ID NO: 835 TRBV7-9*01-3′ ggttctctgcagagaggcctaagggatctttctccaccttggagatccagcgcacagagc agggggactcggccatgtatctctgtgccagcagcttagc SEQ ID NO: 836 TRBV7-9*02-5′ gatactggagtctcccagaaccccagacacaacatcacaaagaggggacagaatgtaact ttcaggtgtgatccaatttctgaacacaaccgcctttatt SEQ ID NO: 837 TRBV7-9*02-3′ tcggttctctgcagagaggcctaagggatctttctccaccttggagatccagcgcacaga gcagggggactcggccatgtatctctgtgccagcagctta SEQ ID NO: 838 TRBV7-9*03-5′ gatactggagtctcccaggaccccagacacaagatcacaaagaggggacagaatgtaact ttcaggtgtgatccaatttctgaacacaaccgcctttatt SEQ ID NO: 839 TRBV7-9*03-3′ tgatcggttctctgcagagaggcctaagggatctttctccaccttggagatccagcgcac agagcagggggactcggccatgtatctctgtgccagcagc SEQ ID NO: 840 TRBV7-9*04-5′ atatctggagtctcccacaaccccagacacaagatcacaaagaggggacagaatgtaact ttcaggtgtgatccaatttctgaacacaaccgcctttatt SEQ ID NO: 841 TRBV7-9*04-3′ tcggatctctgcagagaggcctaagggatctttctccaccttggagatccagcgcacaga gcagggggactcggccatgtatctctgtgccagcagctct SEQ ID NO: 842 TRBV7-9*05-5′ gatactggagtctcccagaaccccagacacaagatcacaaagaggggacagaatgtaact ttcaggtgtgatccaatttctgaacacaaccgcctttatt SEQ ID NO: 843 TRBV7-9*05-3′ tcggttctctgcagagaggcctaagggatctctctccaccttggagatccagcgcacaga gcagggggactcggccatgtatctctgtgccagcaccaaa SEQ ID NO: 844 TRBV7-9*06-5′ gatactggagtctcccagaaccccagacacaagatcacaaagaggggacagaatgtaact ttcaggtgtgatccaatttctgaacacaaccgcctttatt SEQ ID NO: 845 TRBV7-9*06-3′ tcggttctctgcagagaggcctaagggatctctttccaccttggagatccagcgcacaga gcagggggactcggccatgtatctctgtgccagcacgttg SEQ ID NO: 846 TRBV7-9*07-5′ cacaaccgcctttattggtaccgacagaccctggggcagggcccagagtttctgacttac ttccagaatgaagctcaactagaaaaatcaaggctgctca SEQ ID NO: 847 TRBV7-9*07-3′ gttctctgcagagaggcctaagggatctttctccaccttggagatccagcgcacagagga gggggactcggccatgtatctctgtgccagcagcagcagt SEQ ID NO: 848 TRBV8-1*01-5′ gaggcagggatcagccagataccaagatatcacagacacacagggaaaaagatcatcctg aaatatgctcagattaggaaccattattcagtgttctgtt SEQ ID NO: 849 TRBV8-1*01-3′ ggaagggtacaatgtctctggaaacaagctcaagcattttccctcaaccctggagtctac tagcaccagccagacctctgtacctctgtggcagtgcatc SEQ ID NO: 850 TRBV8-2*01-5′ gatgctgggatcacccagatgccaagatatcacattgtacagaagaaagagatgatcctg gaatgtgctcaggttaggaacagtgttctgatatcgacag SEQ ID NO: 851 TRBV8-2*01-3′ agaggggtactgtgtttcttgaaacaagcttgagcatttccccaatcctggcatccacca gcaccagccagacctatctgtaccactgtggcagcacatc SEQ ID NO: 852 TRBV9*01-5′ gattctggagtcacacaaaccccaaagcacctgatcacagcaactggacagcgagtgacg ctgagatgctcccctaggtctggagacctctctgtgtact SEQ ID NO: 853 TRBV9*01-3′ cgattctccgcacaacagttccctgacttgcactctgaactaaacctgagctctctggag ctgggggactcagctttgtatttctgtgccagcagcgtag SEQ ID NO: 854 TRBV9*02-5′ gattctggagtcacacaaaccccaaagcacctgatcacagcaactggacagcgagtgacg ctgagatgctcccctaggtctggagacctctctgtgtact SEQ ID NO: 855 TRBV9*02-3′ cgattctccgcacaacagttccctgacttgcactctgaactaaacctgagctctctggag ctgggggactcagctttgtatttctgtgccagcagcgtag SEQ ID NO: 856 TRBV9*03-5′ gattctggagtcacacaaaccccaaagcacctgatcacagcaactggacagcgagtgacg ctgagatgctcccctaggtctggagacctctctgtgtact SEQ ID NO: 857 TRBV9*03-3′ tgaacgattctccgcacaacagttccctgacttgcactctgaactaaacctgagctctct ggagctgggggactcagctttgtatttctgtgccagcagc SEQ ID NO: 858 TRBVA*01-5′ gaagctgaagccacctagactctaagacacctgattgcagagacaggaaaggagttctca agataagtgccaagatttcatactggttttcacaagaatc SEQ ID NO: 859 TRBVA*01-3′ tccctattgaaaatatttcctggcaaaaaatagaagttctctttggctctgaaatctgca actccctttcaggtgtccctgtgtccttgtaccgtcactc SEQ ID NO: 860 TRBVA/OR9-2*01-5′ gaagctgaagtcacctagactccaagacacctgattgtagagacaggaaaggagttctca ggatatgtgccataatttcatactggtttctacaagaatc SEQ ID NO: 861 TRBVA/OR9-2*01-3′ tccctgttgaaaatatttcccggcaaaaaacagaagttccctttggctctgaaatctgca aagccctttcagatgtccctgtgtccttgtgccgtcactc SEQ ID NO: 862 TRBVB*01-5′ aatgtcaaagtaacacagaccctgagatgaggcaggaaagttgtatcggaatgttttcag actatcaaccagaccaaacgttctggaatccataagatcc SEQ ID NO: 863 TRBVB*01-3′ gactctgagaccctctgcagcagcagcctatcagtgcagccacatcctctctgagcggat atgacaaaccccagggttgaagcgacctaacctatgagcc SEQ ID NO: 864 TRBVC*01-5′ agtgacttctaaattggtctatgaaggagaatctcccccattcctggagtcgcccagtcc agacctctctgtacatttgcaccagcagtttatccacagt SEQ ID NO: 865 TRDV1*01-5′ gcccagaaggttactcaagcccagtcatcagtatccatgccagtgaggaaagcagtcacc ctgaactgcctgtatgaaacaagttggtggtcatattata SEQ ID NO: 866 TRDV1*01-3′ attctgtcaacttcaagaaagcagcgaaatccgtcgccttaaccatttcagccttacagc tagaagattcagcaaagtacttttgtgctcttggggaact SEQ ID NO: 867 TRDV2*01-5′ gccattgagttggtgcctgaacaccaaacagtgcctgtgtcaataggggtccctgccacc ctcaggtgctccatgaaaggagaagcgatcggtaactact SEQ ID NO: 868 TRDV2*01-3′ tttccaaggtgacattgatattgcaaagaacctggctgtacttaagatacttgcaccatc agagagagatgaagggtcttactactgtgcctgtgacacc SEQ ID NO: 869 TRDV2*02-5′ attgagttggtgcctgaacaccaaacagtgcctgtgtcaatagggatccctgccaccctc aggtgctccatgaaaggagaagcgatcggtaactactata SEQ ID NO: 870 TRDV2*02-3′ aatttccaaggtgacattgatattgcaaagaacctggctgtacttaagatacttgcacca tcagagagagatgaagggtcttactactgtgcctgtgaca SEQ ID NO: 871 TRDV2*03-5′ gccattgagttggtgcctgaacaccaaacagtgcctgtgtcaataggggtccctgccacc ctcaggtgctccatgaaaggagaagcgatcggtaactact SEQ ID NO: 872 TRDV2*03-3′ tttccaaggtgacattgatattgcaaagaacctggctgtacttaagatacttgcaccatc agagagagatgaagggtcttactactgtgcctgtgacacc SEQ ID NO: 873 TRDV3*01-5′ tgtgacaaagtaacccagagttccccggaccagacggtggcgagtggcagtgaggtggta ctgctctgcacttacgacactgtatattcaaatccagatt SEQ ID NO: 874 TRDV3*01-3′ gacggttttctgtgaaacacattctgacccagaaagcctttcacttggtgatctctccag taaggactgaagacagtgccacttactactgtgcctttag SEQ ID NO: 875 TRDV3*02-5′ tgtgacaaagtaacccagagttccccggaccagacggtggcgagtggcagtgaggtggta ctgctctgcacttacgacactgtatattcaaatccagatt SEQ ID NO: 876 TRDV3*02-3′ gacggttttctgtgaaacacattctgacccagaaagcctttcacttggtgatctctccag taaggactgaagacagtgccacttactactgtgcctttag SEQ ID NO: 877 TRGV1*01-5′ tcttccaacttggaagggagaacgaagtcagtcaccaggctgactgggtcatctgctgaa atcacctgtgatcttcctggagcaagtaccttatacatcc SEQ ID NO: 878 TRGV1*01-3′ aaagtatgacactggaagcacaaggagcaattggaatttgagactgcaaaatctaattaa aaatgattctgggttctattactgtgccacctgggacagg SEQ ID NO: 879 TRGV10*01-5′ ttatcaaaagtggagcagttccagctatccatttccacggaagtcaagaaaagtattgac ataccttgcaagatatcgagcacaaggtttgaaacagatg SEQ ID NO: 880 TRGV10*01-3′ aggcaagaaagaattctcaaactctcacttcaatccttaccatcaagtccgtagagaaag aagacatggccgtttactactgtgctgcgtggtgggtggc SEQ ID NO: 881 TRGV10*02-5′ ttatcaaaagtggagcagttccagctatccatttccacggaagtcaagaaaagtattgac ataccttgcaagatatcgagcacaaggtttgaaacagatg SEQ ID NO: 882 TRGV10*02-3′ tggaggcaagaaagaattctcaaactctcacttcaatccttaccatcaagtccgtagaga aagaagacatggccgtttactactgtgctgcgtgggatta SEQ ID NO: 883 TRGV11*01-5′ cttgggcagttggaacaacctgaaatatctatttccagaccagcaaataagagtgcccac atatcttggaaggcatccatccaaggctttagcagtaaaa SEQ ID NO: 884 TRGV11*01-3′ ggtaagtaaaaatgctcacacttccacttccactttgaaaataaagttcttagagaaaga agatgaggtggtgtaccactgtgcctgctggattaggcac SEQ ID NO: 885 TRGV11*02-5′ cttgggcagttggaacaacctgaaatatctatttccagaccagcaaataagagtgcccac atatcttggaaggcatccatccaaggctttagcagtaaaa SEQ ID NO: 886 TRGV11*02-3′ gataagtaaaaatgctcacacttccacttccactttgaaaataaagttcttagagaaaga agatgaggtggtgtaccactgtgcctgctggattaggcac SEQ ID NO: 887 TRGV2*01-5′ tcttccaacttggaagggagaacgaagtcagtcatcaggcagactgggtcatctgctgaa atcacttgtgatcttgctgaaggaagtaacggctacatcc SEQ ID NO: 888 TRGV2*01-3′ gtattatacttacgcaagcacaaggaacaacttgagattgatactgcgaaatctaattga aaatgactctggggtctattactgtgccacctgggacggg SEQ ID NO: 889 TRGV2*02-5′ tcttccaacttggaagggagaacgaagtcagtcatcaggcagactgggtcatctgctgaa atcacttgtgatcttgctgaaggaagtaacggctacatcc SEQ ID NO: 890 TRGV2*02-3′ gaagtattatacttacgcaagcacaaggaacaacttgagattgatactgcaaaatctaat tgaaaatgactctggggtctattactgtgccacctgggac SEQ ID NO: 891 TRGV3*01-5′ tcttccaacttggaagggagaacgaagtcagtcaccaggcagactgggtcatctgctgaa atcacttgcgatcttactgtaacaaataccttctacatcc SEQ ID NO: 892 TRGV3*01-3′ gtattatactcatacacccaggaggtggagctggatattgagactgcaaaatctaattga aaatgattctggggtctattactgtgccacctgggacagg SEQ ID NO: 893 TRGV3*02-5′ tcttccaacttggaagggagaacgaagtcagtcaccaggcagactgggtcatctgctgaa atcacttgcgatcttactgtaacaaataccttctacatcc SEQ ID NO: 894 TRGV3*02-3′ agtattatactcatacacccaggaggtggagctggatattgagactgcaaaatctaattg aaaatgattctggggtctattactgtgccacctgggacag SEQ ID NO: 895 TRGV4*01-5′ tcttccaacttggaagggagaacgaagtcagtcatcaggcagactgggtcatctgctgaa atcacttgtgatcttgctgaaggaagtaccggctacatcc SEQ ID NO: 896 TRGV4*01-3′ gtatgatacttatggaagcacaaggaagaacttgagaatgatactgcgaaatcttattga aaatgactctggagtctattactgtgccacctgggatggg SEQ ID NO: 897 TRGV4*02-5′ tcttccaacttggaagggagaacgaagtcagtcatcaggcagactgggtcatctgctgaa atcacttgtgatcttgctgaaggaagtaccggctacatcc SEQ ID NO: 898 TRGV4*02-3′ gtatgatacttacggaagcacaaggaagaacttgagaatgatactgcgaaatcttattga aaatgactctggagtctattactgtgccacctgggatggg SEQ ID NO: 899 TRGV5*01-5′ tcttccaacttggaagggggaacgaagtcagtcacgaggccgactaggtcatctgctgaa atcacttgtgaccttactgtaataaatgccttctacatcc SEQ ID NO: 900 TRGV5*01-3′ gtattatactcatacacccaggaggtggagctggatattgatactacgaaatctaattga aaatgattctggggtctattactgtgccacctgggacagg SEQ ID NO: 901 TRGV5P*01-5′ tcttccaacttggaagggagaatgaagtcagtcaccaggccgactgggtcatctgctgaa atcacttgtgaccttactgtaataaatgccgtctacatcc SEQ ID NO: 902 TRGV5P*01-3′ gtattatactcatacaccgaggaggtggagctggaatttgagactgcaaaatctaattga aaatgattctggggtctattactgtgccacctggggcagg SEQ ID NO: 903 TRGV5P*02-5′ tcttccaacttggaagggagaatgaagtcagtcaccaggccgactgggtcatctgctgaa atcacttgtgaccttactgtaataaatgccgtctacatcc SEQ ID NO: 904 TRGV5P*02-3′ gtattatactcatacaccgaggaggtggagctggaatttgagactgcaaaatctaattga aaatgattctggggtctattactgtgccacctggggcagg SEQ ID NO: 905 TRGV6*01-5′ tctactaacttggaagcgaaaataaagtcaggcaccaggcagatggggtcatctgctgta atcacctgtgatcttcctgtagaaaatgccttctacatcc SEQ ID NO: 906 TRGV6*01-3′ gcatgatacttatggaagtagaaggataagctggaaatttatacctccaaaactaaatga aaatgcctctggggtctattactgtgccacctaggacagg SEQ ID NO: 907 TRGV6*02-5′ tctactaacttggaagcgaaaataaagtcaggcaccaggcagatggggtcatctgctgta atcacctgtgatcttcctgtagaaaatgccttctacatcc SEQ ID NO: 908 TRGV6*02-3′ gcatgatacttatggaagtagaaggataagctggaaatttatacctccaaaactaaatga aaatgcctctggggtctattactgtgccacctaggacagg SEQ ID NO: 909 TRGV7*01-5′ tcttccaacttgcaagggagaaggaagtcagtcaccaggccagctgggtcatctgctgta atcacttgtgatcttactgtaataaataccttctacatcc SEQ ID NO: 910 TRGV7*01-3′ agtattttacttatgcaagcatgaggaggagctggaaattgatactgcaaaatctaattg aaaatgattctggatctattactgtgccacctgggacagg SEQ ID NO: 911 TRGV8*01-5′ tcttccaacttggaagggagaacaaagtcagtcaccaggccaactgggtcatcagctgta atcacttgtgatcttcctgtagaaaatgccgtctacaccc SEQ ID NO: 912 TRGV8*01-3′ gtatcatacttatgcaagcacagggaagagccttaaatttatactggaaaatctaattga acgtgactctggggtctattactgtgccacctgggatagg SEQ ID NO: 913 TRGV9*01-5′ gcaggtcacctagagcaacctcaaatttccagtactaaaacgctgtcaaaaacagcccgc ctggaatgtgtggtgtctggaataacaatttctgcaacat SEQ ID NO: 914 TRGV9*01-3′ tgaggtggataggatacctgaaacgtctacatccactctcaccattcacaatgtagagaa acaggacatagctacctactactgtgccttgtgggaggtg SEQ ID NO: 915 TRGV9*02-5′ gcaggtcacctagagcaacctcaaatttccagtactaaaacgctgtcaaaaacagcccgc ctggaatgtgtggtgtctggaataaaaatttctgcaacat SEQ ID NO: 916 TRGV9*02-3′ tgaggtggataggatacctgaaacgtctacatccactctcaccattcacaatgtagagaa acaggacatagctacctactactgtgccttgtgggaggtg SEQ ID NO: 917 TRGVA*01-5′ ctcatcaggccggagcagctggcccatgtcctggggcactagggaagcttggtcatcctg cagtgcgtggtccgcaccaggatcagctacacccactggt SEQ ID NO: 918 TRGVA*01-3′ agataaaatcatagccaaggatggcagcagctctatcttggcagtactgaagttggagac aggcatcgagggcatgaactactgcacaacctgggccctg SEQ ID NO: 919 TRGVB*01-5′ tttaaagcaataaaaaatgtcaactacatttttgtcaacagagcaacagataaaagtgtc taggtatcttgtgtggtgtccactgaagactttgtaaata SEQ ID NO: 920 TRGVB*01-3′ cttgaggcaagaacaaattttcaaatgtctacttcagtctttaccataaacttcatagga aaggaagatgaggccatttactactgcactgcttaggacc SEQ ID NO: 921 TRAJ1*01 aatagagacacggggcatggtatgaaagtattacctcccagttgcaatttggcaaaggaa ccagagtttccacttctccccgtacgtctgcccatgccca SEQ ID NO: 922 TRAJ10*01 gaggcatcaaacactgtgatactcacgggaggaggaaacaaactcacctttgggacaggc actcagctaaaagtggaactcagtaagtatgagattctat SEQ ID NO: 923 TRAJ11*01 tatggggatttgctatagtgtgaattcaggatacagcaccctcacctttgggaaggggac tatgcttctagtctctccaggtacatgttgaccccatccc SEQ ID NO: 924 TRAJ12*01 actgactaagaaacactgtgggatggatagcagctataaattgatcttcgggagtgggac cagactgctggtcaggcctggtaagtaaggtgtcagagag SEQ ID NO: 925 TRAJ13*01 aaggcaggcattacagtgtgaattctgggggttaccagaaagttacctttggaattggaa caaagctccaagtcatcccaagtgagtccaatttcctatg SEQ ID NO: 926 TRAJ13*02 aaaggcaggcattacagtgtgaattctgggggttaccagaaagttacctttggaactgga acaaagctccaagtcatcccaagtgagtccaatttcctat SEQ ID NO: 927 TRAJ14*01 tttgtcaggcagcacagtgctgtgatttatagcacattcatctttgggagtgggacaaga ttatcagtaaaacctggtaagtaggcaatatgtcactaaa SEQ ID NO: 928 TRAJ15*01 cagggcctcatttcactgtgccaaccaggcaggaactgctctgatctttgggaagggaac caccttatcagtgagttccagtaagtacctgataattatt SEQ ID NO: 929 TRAJ15*02 cagggcctcatttcactgtgccaaccaggcaggaactgctctgatctttgggaagggaac ccacctatcagtgagttccagtaagtacctgataattatt SEQ ID NO: 930 TRAJ16*01 tggtacaatagatcactgtgggttttcagatggccagaagctgctctttgcaaggggaac catgttaaaggtggatcttagtaagtattattactaatga SEQ ID NO: 931 TRAJ17*01 cctgtggtttttgctgggccttaaatcattgtgtgatcaaagctgcaggcaacaagctaa cttttggaggaggaaccagggtgctagttaaaccaagtga SEQ ID NO: 932 TRAJ18*01 aggggaccagcattgtgccgacagaggctcaaccctggggaggctatactttggaagagg aactcagttgactgtctggcctggtgagtgagtcgctttc SEQ ID NO: 933 TRAJ19*01 ttttgcagaggacagatgtggctatcaaagattttacaatttcacctttggaaagggatc caaacataatgtcactccaagtaagtgagcagccttttgt SEQ ID NO: 934 TRAJ2*01 tggtgtcacctacggtatgaatactggaggaacaattgataaactcacatttgggaaagg gacccatgtattcattatatctggtgagtcatcccaggtg SEQ ID NO: 935 TRAJ20*01 tgtaggcgacctcgcactgtggttctaacgactacaagctcagctttggagccggaacca cagtaactgtaagagcaagtaagtaagaaagaaaagtcca SEQ ID NO: 936 TRAJ21*01 tgtaatgccaataaacatggtgtacaacttcaacaaattttactttggatctgggaccaa actcaatgtaaaaccaagtaagttatagttgcctagaaga SEQ ID NO: 937 TRAJ22*01 gttgagcaaatcatagtgtttcttctggttctgcaaggcaactgacctttggatctggga cacaattgactgttttacctggtaggctgcctcaattaaa SEQ ID NO: 938 TRAJ23*01 aggatatgtaacacagtgtgatttataaccagggaggaaagcttatcttcggacagggaa cggagttatctgtgaaacccagtaagtataaaattgtatc SEQ ID NO: 939 TRAJ23*02 gactggatgtgtttttgacaggatatgtaacacagtgtgatttataaccagggaggaaag cttatcttcggacagggaacggagctatctgtgaaaccca SEQ ID NO: 940 TRAJ24*01 gaggtgtttgtcacagtgtgacaactgacagctgggggaaattcgagtttggagcaggga cccaggttgtggtcaccccaggtaagcccattcctggagc SEQ ID NO: 941 TRAJ24*02 gaggtgtttgtcacagtgtgacaactgacagctgggggaaattgcagtttggagcaggga cccaggttgtggtcaccccaggtaagccccattccctgga SEQ ID NO: 942 TRAJ25*01 atgctgagataatcactatgcagaaggacaaggcttctcctttatctttgggaaggggac aaggctgcttgtcaagccaagtaagtgacatataatttat SEQ ID NO: 943 TRAJ26*01 ctgagcccagaaacactgtggggataactatggtcagaattttgtctttggtcccggaac cagattgtccgtgctgccctgtaagtacagttaagtggag SEQ ID NO: 944 TRAJ27*01 caatagcactaaagactgtgtaacaccaatgcaggcaaatcaacctttggggatgggact acgctcactgtgaagccaagtaagttgtgttcttctttgc SEQ ID NO: 945 TRAJ28*01 agaaaggaaactctgtgcatactctggggctgggagttaccaactcactttcgggaaggg gaccaaactctcggtcataccaagtaagttcttctttctg SEQ ID NO: 946 TRAJ29*01 ttatggaggaaatcactgtgggaattcaggaaacacacctcttgtctttggaaagggcac aagactttctgtgattgcaagtaagtgtttctagccatcc SEQ ID NO: 947 TRAJ3*01 aaagaccttacccacagtgggggtacagcagtgcttccaagataatctttggatcaggga ccagactcagcatccggccaagtaagtagaatgaagcagg SEQ ID NO: 948 TRAJ30*01 gttatggtcccaatcacagtgtgaacagagatgacaagatcatctttggaaaagggacac gacttcatattctccccagtaagtgctgtttatgtgattt SEQ ID NO: 949 TRAJ31*01 agtaaaggcaggaagtgctgtggaataacaatgccagactcatgtttggagatggaactc agctggtggtgaagcccagtaagtggccatgttttattga SEQ ID NO: 950 TRAJ32*01 ggctctgaaggactgtgtgaattatggcggtgctacaaacaagctcatctttggaactgg cactctgcttgctgtccagccaagtacgtaagtagtggca SEQ ID NO: 951 TRAJ32*02 gtgattcagccacctacctctgtgccgatggtggtgctacaaacaagctcatctttggaa ctggcactctgcttgctgtccagccaaatatccagaaccc SEQ ID NO: 952 TRAJ33*01 gttaaggtttttgtgtctgtgtggatagcaactatcagttaatctggggcgctgggacca agctaattataaagccaggtaagtctcagagatgtgactg SEQ ID NO: 953 TRAJ34*01 aggtttttgtagatctcagtatcactgtgtcttataacaccgacaagctctttgggactg ggaccagattacaagtctttccaagt SEQ ID NO: 954 TRAJ35*01 taaaagaatgagccattgtggataggctttgggaatgtgctgcattgcgggtccggcact caagtgattgttttaccacgtaagtatatcttttctcatt SEQ ID NO: 955 TRAJ36*01 tactgggcagaaacactgtgtcaaactggggcaaacaacctcttctttgggactggaacg agactcaccgttattccctgtaagtccttacctcttgaca SEQ ID NO: 956 TRAJ37*01 aaagtacagcattagagtgtggctctggcaacacaggcaaactaactttgggcaagggac aactttacaagtaaaaccaggtaggtctggatgtttcca SEQ ID NO: 957 TRAJ37*02 ctcagcggtgtacttctgtgctcttcatggctctagcaacacaggcaaactaatctttgg gcaagggacaactttacaagtaaaaccagatatccagaac SEQ ID NO: 958 TRAJ38*01 aaagctttctatgactgtgtaatgctggcaacaaccgtaagctgatttggggattgggaa caagcctggcagtaaatccgagtgagtcttcgtgttaact SEQ ID NO: 959 TRAJ39*01 cagccgaagatcactgtgtgaataataatgcaggcaacatgctcacctttggagggggaa caaggttaatggtcaaaccccgtgagtatctctgctgaat SEQ ID NO: 960 TRAJ4*01 aagcaccatctgattgtgtgttttctggtggctacaataagctgatttttggagcaggga ccaggctggctgtacacccatgtgagtatgaccctgcaag SEQ ID NO: 961 TRAJ40*01 tatgttggtttatgtagagacacataacdactgtgactacctcaggaacctacaaataca tctttggaacaggcaccaggctgaaggttttagcaagt SEQ ID NO: 962 TRAJ41*01 ttagggagaacgcactgtggaactcaaattccgggtatgcactcaacttcggcaaaggca cctcgctgttggtcacaccccgtgagtttttgtggtttac SEQ ID NO: 963 TRAJ42*01 agccccataggactgtgtgaattatggaggaagccaaggaaatctcatctttggaaaagg cactaaactctctgttaaaccaagtaagtgttggggattc SEQ ID NO: 964 TRAJ43*01 ttgttagagcatgtattactgtgacaataacaatgacatgcgctttggagcagggaccag actgacagtaaaaccaagtaagttgggggaatgggtcaat SEQ ID NO: 965 TRAJ44*01 aggtttctgttatgaagcatctcacagtgtaaataccggcactgccagtaaactcacctt tgggactggaacaagacttcaggtcacgctcggt SEQ ID NO: 966 TRAJ45*01 agggttggcccagagtgtgtattcaggaggaggtgctgacggactcacctttggcaaagg gactcatctaatcatccagccctgtaagtgcttttgcctg SEQ ID NO: 967 TRAJ46*01 aagctgctgacagccgtgagaagaaaagcagcggagacaagctgacttttgggaccggga ctcgtttagcagttaggcccagtaagtctgagcagaaagt SEQ ID NO: 968 TRAJ47*01 gtagaggagtttgacgctgtgtggaatatggaaacaaactggtctttggcgcaggaacca ttctgagagtcaagtcctgtgagtataaaacacactcaag SEQ ID NO: 969 TRAJ47*02 gtgtactattgcatctcggccctggaatatggaaacaagctggtctttggcgcaggaacc attctgagagtcaagtcctatatccagaaccctgaccctg SEQ ID NO: 970 TRAJ48*01 atgacttagaacactgtgtatctaactttggaaatgagaaattaacctttgggactggaa caagactcaccatcatacccagtaagttcttcatccttgg SEQ ID NO: 971 TRAJ49*01 tgttgagcttcctatcacagtggaacaccggtaaccagttctattttgggacagggacaa gtttgacggtcattccaagtaagtcaaagaaaattttcca SEQ ID NO: 972 TRAJ5*01 tactgtgatgtaccagggtgtggacacgggcaggagagcacttacttttgggagtggaac aagactccaagtgcaaccaagtaagtacccaaacttaggc SEQ ID NO: 973 TRAJ50*01 taaaggtttggatggctgtgtgaaaacctcctacgacaaggtgatatttgggccagggac aagcttatcagtcattccaagtaagtgtccctggggtgct SEQ ID NO: 974 TRAJ51*01 aaactccctgaagcagggagatgcgtgacagctatgagaagctgatatttggaaaggaga catgactaactgtgaagccaagcaagctggaaagacctaa SEQ ID NO: 975 TRAJ52*01 gcctccagtgcagtgctaatgctggtggtactagctatggaaagctgacatttggacaag ggaccatcttgactgtccatccaagtaagtgtaacaagac SEQ ID NO: 976 TRAJ53*01 agccttctgtggctgtgagaatagtggaggtagcaactataaactgacatttggaaaagg aactctcttaaccgtgaatccaagtaagtttgaagggagt SEQ ID NO: 977 TRAJ54*01 taaagcctcgtgctgtggtgtaattcagggagcccagaagctggtatttggccaaggaac caggctgactatcaacccaagtaagtatgacagggtgaag SEQ ID NO: 978 TRAJ55*01 gaggatggatccctgttagtgacaagtgctggtaatgctcctgttggggaaaggggatga gtacaaaaataaatccaagtaagtgtggagggacaagaag SEQ ID NO: 979 TRAJ56*01 agatcctcgtgtcattgtgttatactggagccaatagtaagctgacatttggaaaaggaa taactctgagtgttagaccaggtatgttttaatgaatgtt SEQ ID NO: 980 TRAJ57*01 aagcagtctgtgggggtgtaactcagggcggatctgaaaagctggtctttggaaagggaa cgaaactgacagtaaacccatgtaagtctgaataatgctt SEQ ID NO: 981 TRAJ58*01 aagcccctcagcacagtgtttaagaaaccagtggctctaggttgacctttggggaaggaa cacagctcacagtgaatcctggtaagtggaggggagcatt SEQ ID NO: 982 TRAJ59*01 atgtaaaggcagcagctcctgtgggaaggaaggaaacaggaaatttacatttggaatggg gacgcaagtgagagtgaagctatctttaaaccaaaggtgt SEQ ID NO: 983 TRAJ6*01 caggttttatcaaaggctgtcctcactgtgtgcatcaggaggaagctacatacctacatt tggaagaggaaccagccttattgttcatccgtgtaagt SEQ ID NO: 984 TRAJ60*01 gtaaagggcctgggcactatgtgaagatcacctagatgctcaactttgggaaggggactg agttaattgtgagcctgggtgagtacctcaactccagagg SEQ ID NO: 985 TRAJ61*01 taaaggtgcccactcctgtgggtaccgggttaataggaaactgacatttggagccaacac tagaggaatcatgaaactcagcaagtaatatttggcagaa SEQ ID NO: 986 TRAJ7*01 tgtaatacacttacacagtgtgactatgggaacaacagactcgcttttgggaaggggaac caagtggtggtcataccaagtaagtgagctgggatcctcc SEQ ID NO: 987 TRAJ8*01 tacagagttatgtcagagtgtgaacacaggctttcagaaacttgtatttggaactggcac ccgacttctggtcagtccaagtaagtcaaatctgcagaaa SEQ ID NO: 988 TRAJ9*01 cgcagtgcaaatcactgtgggaaatactggaggcttcaaaactatctttggagcaggaac aagactatttgttaaagcaagtaagttccatgaaataacc SEQ ID NO: 989 TRBJ1-1*01 ttttcaccttgacccctgtcactgtgtgaacactgaagctttctttggacaaggcaccag actcacagttgtaggtaagacatttttcaggttcttttgc SEQ ID NO: 990 TRBJ1-2*01 ttttagagtggctatattcttatgtgctaactatggctacaccttcggttcggggaccag gttaaccgttgtaggtaaggctgggggtctctaggagggg SEQ ID NO: 991 TRBJ1-3*01 tttgaagtggccctgggaggctgtgctctggaaacaccatatattttggagagggaagtt ggctcactgttgtaggtgagtaagtcaaggctggacagct SEQ ID NO: 992 TRBJ1-4*01 ttccttccagtctttaatgttgtgcaactaatgaaaaactgttttttggcagtggaaccc agctctctgtcttgggtatgtaaaagacttctttcgggat SEQ ID NO: 993 TRBJ1-5*01 tttgccacactcatgatgcactgtgtagcaatcagccccagcattttggtgatgggactc gactctccatcctaggtaagttggcagaatcagggtggta SEQ ID NO: 994 TRBJ1-6*01 ttatctaagcctctgcagctgtgctcctataattcacccctccactttgggaatgggacc aggctcactgtgacaggtatgggggctccactcttgactc SEQ ID NO: 995 TRBJ1-6*02 ttatctaagcctctgcagctgtgctcctataattcacccctccactttgggaacgggacc aggctcactgtgacaggtatgggggctccactcttgactc SEQ ID NO: 996 TRBJ2-1*01 ttctgggcagccccttcccactgtgctcctacaatgagcagttcttcgggccagggacac ggctcaccgtgctaggtaagaagggggctccaggtgggag SEQ ID NO: 997 TRBJ2-2*01 tgcgccagggtccccagggctgtgcgaacaccggggagctgttttttggagaaggctcta ggctgaccgtactgggtaaggaggcggctggggctccgga SEQ ID NO: 998 TRBJ2-2P*01 agctgccccactctgagaggggctgtgctgagaggcgctgctgggcgtctgggcggagga ctcctggttctgggtgctgggagagcgatggggctctcag SEQ ID NO: 999 TRBJ2-3*01 ttttgtcctgggcctccaggctgtgagcacagatacgcagtattttggcccaggcacccg gctgacagtgctcggtaagcgggggctcccgctgaagccc SEQ ID NO: 1001 TRBJ2-4*01 ttctgtgccgcgtctcggggctgtgagccaaaaacattcagtacttcggcgccgggaccc ggctctcagtgctgggtaagctggggccgccgggggaccg SEQ ID NO: 1002 TRBJ2-5*01 tttttgtgcggggctcgggggccgtgaccaagagacccagtacttcgggccaggcacgcg gctcctggtgctcggtgagcgcgggctgctggggcgcggg SEQ ID NO: 1003 TRBJ2-6*01 ttgcggggagtccccgggctgtgctctggggccaacgtcctgactttcggggccggcagc aggctgaccgtgctgggtgagttttcgcgggaccacccgg SEQ ID NO: 1004 TRBJ2-7*01 tttgcatgcgggggtgcacctccgtgctcctacgagcagtacttcgggccgggcaccagg ctcacggtcacaggtgagattcgggcgtctccccaccttc SEQ ID NO: 1005 TRBJ2-7*02 tttgcatgcggggatgcacctccgtgctcctacgagcagtacgtcgggccgggcaccagg ctcacggtcacaggtgagattcgggcgtctccccaccttc SEQ ID NO: 1006 TRDJ1*01 ttttggaacgtcctcaagtgctgtgacaccgataaactcatctttggaaaaggaacccgt gtgactgtggaaccaagtaagtaactcattatttatctga SEQ ID NO: 1007 TRDJ2*01 tttttcgtaatgacgcctgtggtagtgctttgacagcacaactcttctttggaaagggaa cacaactcatcgtggaaccaggtaagttatgcattttact SEQ ID NO: 1008 TRDJ3*01 tgaggcactgtcataatgtgctcctgggacacccgacagatgtttttcggaactggcatc aaactcttcgtggagccccgtgagttgatctttttcctat SEQ ID NO: 1009 TRDJ4*01 atgagacatacaaaaaggtaatgccgccccagacccctgatctttggcaaaggaacctat ctggaggtacaacaac SEQ ID NO: 1010 TRGJ1*01 ttttgatatggactgaatcactgtggaattattataagaaactctttggcagtggaacaa cactggttgtcacaggtaagtatcggaagaatacaacatt SEQ ID NO: 1011 TRGJ1*02 tactgtgccttgtgggagtgcttattataagaaactctttggcagtggaacaacacttgt tgtcacaggt SEQ ID NO: 1012 TRGJ2*01 ttttgatatggactgaatcactgtggaattattaagaaactctttggcagtggaacaac acttgttgtcacaggtaagtatcggaagaatacaacatt SEQ ID NO: 1013 TRGJP*01 ataaaggcttctcaggtggtgggcaagagttgggcaaaaaaatcaaggtatttggtcccg gaacaaagcttatcattacaggtaagttttctttaaattt SEQ ID NO: 1014 TRGJP1*01 gatttttctagaagcttagaccggtgtgataccactggttggttcaagatatttgctgaa gggactaagctcatagtaacttcacctggtaagt SEQ ID NO: 1015 TRGJP2*01 gatttttgtagaagcttagaccagtgtgatagtagtgattggatcaagacgtttgcaaaa gggactaggctcatagtaacttcgcctggtaagt

TABLE 4 SEQ ID NO Name Sequence SEQ ID NO: 1015 TRAV1-1*02-RIGHT caggtcgtttttcttcattccttagtcgctctgatagttatggttacctccttctac aggagctccagatgaaagactctgcctcttacttctgcgctgt SEQ ID NO: 1016 TRAV1-2*02-RIGHT catctgggttcaacgggctgttctggtaccagcaacatgctggcgaagcacccacat ttctgtcttacaatgttctggatggtctggaggagaaaggtcg SEQ ID NO: 1017 TRAV12-1*02-RIGHT acagcacacgtcaatagagccagccagtatatttccctgctcatcagagactccaag ctcagtgattcagccacctacctctgtgtggtgaacattcgcc SEQ ID NO: 1018 TRAV12-2*02-RIGHT gtttacagcacagctcaataaagccagccagtatgtttctctgctcatcagagactc ccagcccagtgattcagccacctacctctgtgccgtgtaccac SEQ ID NO: 1019 TRAV12-2*03-RIGHT aaggtttacagcacagctcaataaagccagccagtatgtttctctgctcatcagaga ctcccagcccagtgattcagccacctacctctgtgccgtgaac SEQ ID NO: 1020 TRAV12-3*02-RIGHT aggtttacagcacaggtcgataaatccagcaagtatatctccttgttcatcagagac tcacagcccagtgattcagccacctacctctgtgcaatgagcg SEQ ID NO: 1021 TRAV13-1*02-RIGHT tgttacattgaacaagacagccaaacatttctccctgcacatcacagagacccaacc tgaagactcggctgtctacttctgtgcagcaagtaggaaggac SEQ ID NO: 1022 TRAV13-1*03-RIGHT gcttattatagacattcgttcaaatgtgggcgaaaagaaagaccaacgaattgctgt tacattgaacaagacagccaaacatttctccctgcagatcaca SEQ ID NO: 1023 TRAV13-2*02-RIGHT caaagagtcaccgttttattgaataagacagtgaaacatctctctctgcaaattgca gctactcaacctggagactcagctgtctacttttgtgcagaga SEQ ID NO: 1024 TRAV14/DV4*03-RIGHT aggtcgctactcattgaatttccagaaggcaagaaaatccgccaaccttgtcatctc cgcttcacaactgggggactcagcaatgtatttctgtgcaatg SEQ ID NO: 1025 TRAV14/DV4*04-RIGHT gcaacagaaggtcgctactcattgaatttccagaaggcaagaaaatccgccaacctt gtcatctccgcttcacaactgggggactcagcaatgtacttct SEQ ID NO: 1026 TRAV2*02-RIGHT gggacgatacaacatgacctatgaacggttctcttcatcgctgctcatcctccaggt gcgggaggcagatgctgctgtttactactgtgctgtggcctgg SEQ ID NO: 1027 TRAV20*02-RIGHT aaaggagaaagaaaggctaaaagccacattaacaaagaaggaaagctttctgcacat cacagcccctaaacctgaagactcagccacttatctctgtgct SEQ ID NO: 1028 TRAV20*03-RIGHT agaaaaggagaaagaaaggctaaaagccacattaacaaagaaggaaagctttctgca catcacagcccctaaacctgaagactcagccacttatctctgt SEQ ID NO: 1029 TRAV20*04-RIGHT aaaggagaaagaaaggctaaaagccacattaacaaagaaggaaagctttctgcacat cacagcccctaaacctgaagactcagccacttatctctgtgct SEQ ID NO: 1030 TRAV21*02-RIGHT aagtggaagacttaatgcctcgctggataaatcatcaggacgtagtactttatacat tgcagcttctcagcctggtgactcagccacctacctctgtgct SEQ ID NO: 1031 TRAV23/DV6*02-RIGHT agattcacaatctccttcaataaaagtgccaagcagttctcattgcatatcatggat tcccagcctggagactcagccacctacttctgtgcagcaagcg SEQ ID NO: 1032 TRAV23/DV6*03-RIGHT agattcacaatctccttcaataaaagtgccaagcagttctcattgcatatcatggat tcccagcctggagactcagccacctacttctgtgcagcaagca SEQ ID NO: 1033 TRAV23/DV6*04-RIGHT gaaagaaggaagattcacaatctccttcaataaaagtgccaagcagttctcattgca tatcatggattcccagcctggagactcagccacctacttctgt SEQ ID NO: 1034 TRAV24*02-RIGHT ggacgaataagtgccactcttaataccaaggagggttacagctatttgtacatcaaa ggatcccagcctgaagattcagccacatacctctgtgccttta SEQ ID NO: 1035 TRAV26-1*02-RIGHT ctctgatcatcacagaagacagaaagtccagcaccttgatcctgccccacgctacgc tgagagacactgctgtgtactattgcatcgtcagagattgggt SEQ ID NO: 1036 TRAV26-1*03-RIGHT caatgaaatggcctctctgatcatcacagaagacagaaagtccagcaccttgatcct gccccacgctacgctgagagacactgctgtgtactattgcatc SEQ ID NO: 1037 TRAV26-2*02-RIGHT ccctcccagggtccagagtacgtgattcatggtcttacaagcaatgtgaacaacaga atggcctgtgtggcaatcgctgaagacagaaagtccagtacct SEQ ID NO: 1038 TRAV27*02-RIGHT tgaagagactaacctttcagtttggtgatgcaagaaaggacagttctctccacatca ctgcggcccagcctggtgatacaggccactacctctgtgcagg SEQ ID NO: 1039 TRAV27*03-RIGHT gctgaagagactaacctttcagtttggtgatgcaagaaaggacagttctctccacat cactgcagcccagactggtgatacaggcctctacctctgtgca SEQ ID NO: 1040 TRAV29/DV5*02-RIGHT aagattcactgttttcttaaacaaaagtgccaagcacctctctctcgacattgtgcc ctcccagcctggagactctgcagtgtacttctgtgcagcaagc SEQ ID NO: 1041 TRAV29/DV5*03-RIGHT agattcactgttttcttaaacaaaagtgccaagcacctctctctgcacattgtgccc tcccagcctggagactctgcagtgtacttctgtgcagcaagcg SEQ ID NO: 1042 TRAV3*02-RIGHT ctttgaagctgaatttaacaagagccaaacctccttccacctgaagaaaccatctgc ccttgtgagcgactccgctttgtacttctgtgctgtgagaccc SEQ ID NO: 1043 TRAV30*02-RIGHT tcgtgaaaaaatatctgcttcatttaatgaaaaaaagcagcaaagctccctgtacct tacggcctcccagctcagttactcaggaacctacttctgcggg SEQ ID NO: 1044 TRAV30*03-RIGHT tcatgaaaaaatatctgcttcatttaatgaaaaaaagcggcaaagctccctgtacct tacggcctcccagctcagttactcaggaacctacttctgcggc SEQ ID NO: 1045 TRAV30*04-RIGHT tcctgatgatattactgaagggtggagaacagaagcgtcatgaaaaaatatctgctt catttaatgaaaaaaagcagcaaagctccctgtaccttacggc SEQ ID NO: 1046 TRAV35*02-RIGHT aaatggaagactgactgctcagtttggtataaccagaaaggacagcttcctgaatat ctcagcatccatacctagtgatgtaggcatctacttctgtgct SEQ ID NO: 1047 TRAV36/DV7*02-RIGHT ggaagactaagtagcatattagataagaaagaacttttcagcatcctgaacatcaca gccacccagaccggagactcggccgtctacctctgtgctgtgg SEQ ID NO: 1048 TRAV36/DV7*03-RIGHT gtcaggaagactaagtagcatattagataagaaagaacttttcagcatcctgaacat cacagccacccagaccggagactcggccgtctacctctgtgct SEQ ID NO: 1049 TRAV36/DV7*04-RIGHT tcaggaagactaagtagcatattagataagaaagaacttttcagcatcctgaacatc acagccacccagaccggagactcggccgtctacctctgtgctg SEQ ID NO: 1050 TRAV38-1*02-RIGHT gagaatcgtttctctgtgaacttccagaaagcagccaaatccttcagtctcaagatc tcagactcacagctgggggacactgcgatgtatttctgtgctt SEQ ID NO: 1051 TRAV38-1*03-RIGHT aatcgtttctctgtgaacttccagaaagcagccaaatccttcagtctcaagatctca gactcacagctgggggacactgcgatgtatttctgtgctttca SEQ ID NO: 1052 TRAV38-1*04-RIGHT ggagaatcgtttctctgtgaacttccagaaagcagccaaatccttcagtctcaagat ctcagactcacagctgggggacactgcgatgtatttctgtgca SEQ ID NO: 1053 TRAV6*02-RIGHT gaaagaaagactgaaggtcacctttgataccacccttaaacagagtttgtttcatat cacagcctcccagcctgcagactcagctacctacctctgtgct SEQ ID NO: 1054 TRAV6*03-RIGHT gaaagaaagactgaaggtcacctttgataccacccttaaacagagtttgtttcatat cacagcctcccagcctgcagactcagctacctacctctgtgct SEQ ID NO: 1055 TRAV6*04-RIGHT gaaagaaagactgaaggtcacctttgataccacccttaaacagagtttgtttcatgt cacagcctcccagcctgcagactcagctacctacctctgtgct SEQ ID NO: 1056 TRAV6*05-RIGHT gaaagaaagactgaaggtcacctttgataccacccttaaacagagtttgtttcatat cacagcctcccagcctgcagactcagctacctacctctgtgct SEQ ID NO: 1057 TRAV6*06-RIGHT ccaggaagaggccctgttttcttgctactcatacgtgaaaatgagaaagaaaaaagg aaagaaagactgaaggtcacctttgataccacccttaaccaga SEQ ID NO: 1058 TRAV8-1*02-RIGHT ttttcaggggatccactggttaaaggcatcaagggcgttgaggctgaatttataaag agtaaattctcctttaatctgaggaaaccctctgtgcagtgga SEQ ID NO: 1059 TRAV8-2*02-RIGHT tttaagaagagtgaaacctccttccacctgacgaaaccctcagcccatatgagcgac gcggctgagtacttctgtgttgtgacccgtcacgagctttcag SEQ ID NO: 1060 TRAV8-3*02-RIGHT aggctttgaggctgaatttaagaggagtcaatcttccttcaacctgaggaaaccctc tgtgcattggagtgatgctgctgagtacttctgtgctgtggtt SEQ ID NO: 1061 TRAV8-3*03-RIGHT tattaaaggctttgaggctgaatttaagaggagtcaatcttccttcaatctgaggaa accctctgtgcattggagtgatgcgtctgagtacttctgtgct SEQ ID NO: 1062 TRAV8-4*02-RIGHT gaatttaagaagagtgaaacctccttccacctgacaaaaccctcagcccatatgagc gacgcggctgagtacttctgtgctgtgagtgatctcgaaccga SEQ ID NO: 1063 TRAV8-4*03-RIGHT catcaacggttttgaggctgaatttaagaagagtgaaacctccttccacctgacgaa accctcagcccatatgagcgacgcggctgagtacttctgtgct SEQ ID NO: 1064 TRAV8-4*04-RIGHT aggcatcaacggttttgaggctgaatttaagaagagtgaaacctccttccacctgac gaaaccctcagcccatatgagcgacgcggctgagtacttctgt SEQ ID NO: 1065 TRAV8-4*05-RIGHT ggctgaatttaagaagagtgaaacctccttccacctgacgaaaccctcagcccatat gagcgacgcggctgagtacttctgtgctgtgagtgagtctcca SEQ ID NO: 1066 TRAV8-4*06-RIGHT gaatttaagaagagtgaaacctccttccacctgacgaaacccgcagcccatatgagc gacgcggctgagtacttctgtgctgtgagtgatctcgaaccga SEQ ID NO: 1067 TRAV8-4*07-RIGHT acggttttgaggctgaatttaaaaagagtgaaacctccttccacctgacgaaaccct cagcccatatgaccgacccggctgagtacttctgtgctgtgag SEQ ID NO: 1068 TRAV9-2*02-RIGHT caacaaaggttttgaagccacataccgtaaagaaaccacttctttccacttggagaa aggctcagttcaagtgtcagactcagcggtgtacttctgtgct SEQ ID NO: 1069 TRAV9-2*03-RIGHT caacaaaggttttgaagccacataccgtaaggaaaccacttctttccacttggagaa aggctcagttcaagtgtcagactcagcggtgtacttctgtgct SEQ ID NO: 1070 TRAV9-2*04-RIGHT caacaaaggttttgaagccacataccgtaaggaaaccacttctttccacttggagaa aggctcagttcaagtgtcagactcagcggtgtacttctgtgct SEQ ID NO: 1071 TRAV10-1*03-RIGHT ctaacaaaggagaagtctcagatggctacagtgtctctagatcaaacacagaggacc tccccctcactctgtagtctgctgcctcctcccagacatctgt SEQ ID NO: 1072 TRAV10-2*02-RIGHT agataaaggagaagtccccgatggctacgttgtctccagatccaagacagagaattt ccccctcactctggagtcagctacccgctcccagacatctgtg SEQ ID NO: 1073 TRAV10-3*03-RIGHT agaagtctcagatggctatagtgtctctagatcaaagacagaggatttcctcctcac tctggagtccgctaccagctcccagacatctgtgtacttctgt SEQ ID NO: 1074 TRAV10-3*04-RIGHT agaagtctcagatggctatagtgtctctagatcaaagacagaggatttcctcctcac tctggagtccgctaccagctcccagacatctgtgtacttctgt SEQ ID NO: 1075 TRBV11-2*02-RIGHT ggatcgattttctgcagagaggctcaaaggagtagactccactctcaagatccagcc tgcaaagcttgagaactcggccgtgtatctctgtgccagcagt SEQ ID NO: 1076 TRBV11-2*03-RIGHT ggatcgattttctgcagagaggctcaaaggagtagactccactctcaagatccaacc tgcaaagcttgaggactcggccgtgtatctctgtgccagcagc SEQ ID NO: 1077 TRBV11-3*02-RIGHT ggatcgattttctgcagagaggctcaaaggagtagactccactctcaagatccagcc tgcagagcttggggactcggccgtgtatctctgtgccagcagc SEQ ID NO: 1078 TRBV11-3*03-RIGHT ggatcgattttctgcagagaggctcaaaggagtagactccactctcaagatccagcc agcagagcttggggactcggccatgtatctctgtgccagcagc SEQ ID NO: 1079 TRBV12-4*02-RIGHT tcgattctcagctaagatgcctaatgcatcattctccactctgaggatccagccctc agaacccagggactcagctgtgtacttctgtgccagcagttta SEQ ID NO: 1080 TRBV13*02-RIGHT tgatcgattctcagctcaacagttcagtgactatcattctgaactgaacatgagctc cttggagctgggggactcagccctgtacttctgtgccagcagc SEQ ID NO: 1081 TRBV14*02-RIGHT caatcgattcttagctgaaaggactggagggacgtattctactctgaaggtgcagcc tgcagaactggaggattctggagtttatttctgtgccagcagc SEQ ID NO: 1082 TRBV15*02-RIGHT tgataacttccaatccaggaggccgaacacttctttctgctttcttgacatccgctc accaggcctgggggacgcagccatgtacctgtgtgccaccagc SEQ ID NO: 1083 TRBV15*03-RIGHT tgataacttccaatccaggaggccgaacacttctttctgctttctagacatccgctc accaggcctgggggacgcagccatgtaccagtgtgccaccagc SEQ ID NO: 1084 TRBV16*03-RIGHT ggaaagattttcagctaagtgcctcccaaattcaccctgtagccttgagatccaggc tacgaagcttgaggattcagcagtgtatttttgtgccagcagc SEQ ID NO: 1085 TRBV19*03-RIGHT tgaagggtacagcgtctctcgggagaagaaggaatcctttcctctcactgtgacatc ggcccaaaagaacccgacagctttctatctctgtgccagtagc SEQ ID NO: 1086 TRBV2*02-RIGHT tgatcaattctcagttgaaaggcctgatggatcaaatttcactctgaagatccggtc cacaaagctggaggactcagccatgtacttctgtgccagcagt SEQ ID NO: 1087 TRBV2*03-RIGHT tcaattctcagttgagaggcctgatggatcaaatttcactctgaagatccggtccac aaagctggaggactcagccatgtacttctgtgccagcagtgaa SEQ ID NO: 1088 TRBV20-1*02-RIGHT gaaggacaagtttctcatcaaccatgcaagcctgaccttgtccactctgacagtgac cagtgcccatcctgaagacagcagcttctacatctgcagtgct SEQ ID NO: 1089 TRBV20-1*04-RIGHT ggacaagtttctcatcaaccatgcaagcctgaccttgtccactctgacagtgaccag tgcccatcctgaagacagcagcttctacatctgcagtgctagt SEQ ID NO: 1090 TRBV20-1*05-RIGHT ggacaagtttctcatcaaccatgcaagcctgaccttgtccactctgacagtgaccag tgcccatcctgaagacagcagcttctacatctgcagtgctaga SEQ ID NO: 1091 TRBV20-1*06-RIGHT gaaggacaagtttctcatcaaccatgcaagcctgaccttgtccactctgacagtgac cagtgcccatcctgaagacagcagcttctacatctgcagtgct SEQ ID NO: 1092 TRBV20-1*07-RIGHT ggacaagtttctcatcaaccatgcaagcctgaccttgtccactctgacagtgaccag tgcccatcctgaagacagcagcttctacatctgcagtgctaga SEQ ID NO: 1093 TRBV20/OR9-2*02-RIGHT gaaggacaagtttcccatcaaccatccaaacctgaccttctccgctctgacagtgac ctgtgcccatcctgaagacagcagcttctacatctgcagtgct SEQ ID NO: 1094 TRBV23/OR9-2*02-RIGHT gtttttgatttcctttcagaatgaacaagttcttcaagaaatggagatgcacaagaa gcgattctcatctcaatgccccaagaacgcaccctgcagcctg SEQ ID NO: 1095 TRBV24/OR9-2*02-RIGHT cagttgatctattgctcctttgatgtcaaaatatataaacaaaagagagatctctga tggatacagtgtctcttgacaggaacaggctaaattctccctg SEQ ID NO: 1096 TRBV25/OR9-2*02-RIGHT gagttaattccacagagaagggagatctttgctctgagtcaacagtctccagaataa ggatagagcgttttcccctgaccctggagtctgccagcccctc SEQ ID NO: 1097 TRBV29-1*02-RIGHT tgacaagtttcccatcagccgcccaaacctaacattctcaagtctgactgtgagcaa catgagccctgaagacagcagcatatatctctgcagcgttgaa SEQ ID NO: 1098 TRBV29-1*03-RIGHT tgacaagtttcccatcagccgcccaaacctaacattctcaactctgactgtgagcaa catgagccctgaagacagcagcatatatctctgcagcgcgggc SEQ ID NO: 1099 TRBV3-1*02-RIGHT tccaaatcgattctcacctaaatctccagacaaagctaaattaaatcttcacatcaa ttccctggagcttggtgactctgctgtgtatttctgtgccagc SEQ ID NO: 1100 TRBV3-2*03-RIGHT tcgcttctcacctgactctccagacaaagttcatttaaatcttcacatcaattccct ggagcttggtgactctgctgtgtatttctgtgccagcagccaa SEQ ID NO: 1101 TRBV30*02-RIGHT agaatctctcagcctccagaccccaggaccggcagttcatcctgagttctaagaagc tcctcctcagtgactctggcttctatctctgtgcctggagtgt SEQ ID NO: 1102 TRBV30*04-RIGHT ccagaatctctcagcctccagaccccaggaccggcagttcattctgagttctaagaa gctcctcctcagtgactctggcttctatctctgtgcctggagt SEQ ID NO: 1103 TRBV30*05-RIGHT ccagaatctctcagcctccagaccccaggaccggcagttcatcctgagttctaagaa gctccttctcagtgactctggcttctatctctgtgcctgggga SEQ ID NO: 1104 TRBV4-1*02-RIGHT tcgcttctcacctgaatgccccaacagctctctcttaaaccttcacctacacgccct gcagccagaagactcagccctgtatctctgcgccagcagccaa SEQ ID NO: 1105 TRBV4-2*02-RIGHT aagtcgcttctcacctgaatgccccaacagctctcacttatgccttcacctacacac cctgcagccagaagactcggccctgtatctctgtgccagcacc SEQ ID NO: 1106 TRBV4-3*02-RIGHT aagtcgcttctcacctgaatgccccaacagctctcacttatcccttcacctacacac cctgcagccagaagactcggccctgtatctctgcgccagcagc SEQ ID NO: 1107 TRBV4-3*03-RIGHT aagtcgcttctcacctgaatgccccaacagctctcacttattccttcacctacacac cctgcagccagaagactcggccctgtatctctgcgccagcagc SEQ ID NO: 1108 TRBV4-3*04-RIGHT aagtcgcttctcacctgaatgccccaacagctctcacttattccttcacctacacac cctgcagccagaagactcggccctgtatctctgcgccagcagc SEQ ID NO: 1109 TRBV5-1*02-RIGHT tcgattctcagggcgccagttctctaactctcgctctgagatgaatgtgagcacctt ggagctgggggactcggccctttatctttgcgccagcgcttgc SEQ ID NO: 1110 TRBV5-4*02-RIGHT tcctagattctcaggtctccagttccctaattataactctgagctgaatgtgaacgc cttggagctggacgactcggccctgtatctctgtgccagcagc SEQ ID NO: 1111 TRBV5-4*03-RIGHT tcctagattctcaggtctccagttccctaattatagctctgagctgaatgtgaacgc cttggagctggacgactcggccctgtatctctgtgccagcagc SEQ ID NO: 1112 TRBV5-4*04-RIGHT tcctagattctcaggtctccagttccctaattatagctctgagctgaatgtgaacgc cttggagctggacgactcggccctgtatctctgtgccagcagc SEQ ID NO: 1113 TRBV5-5*02-RIGHT tgatcgattctcagctcgccagttccctaactatagctctgagctgaatgtgaacgc cttgttgctgggggactcggccctgtatctctgtgccagcagc SEQ ID NO: 1114 TRBV5-5*03-RIGHT tgatcgattctcagctcgccagttccctaactatagctctgagctgaatgtgaacgc cttgttgctgggggactcggccctgtatctctgtgccagcagc SEQ ID NO: 1115 TRBV5-8*02-RIGHT tcctagattttcaggtcgccagttccctaattatagctctgagctgaatgtgaacgc cttggagctggaggactcggccctgtatctctgtgccagcagc SEQ ID NO: 1116 TRBV6-2*02-RIGHT tggctacaatgtctccagattaaaaaaacagaatttcctgctggggttggagtcggc tgctccctcccaaacatctgtgtacttctgtgccagcagccct SEQ ID NO: 1117 TRBV6-6*03-RIGHT gaatggctacaacgtctccagatcaaccacagaggatttcccgctcaggctggagtt ggctgctccctcccagacatctgtgtacttctgtgccagcagt SEQ ID NO: 1118 TRBV6-6*04-RIGHT tggctacaatgtctccagatcaaccacagaggatttcccgctcaggctggagttggc tgctccctcccagacatctgtgtacttctgtgccagcagtcga SEQ ID NO: 1119 TRBV6-6*05-RIGHT gaatggctacaacgtctccagatcaaccacagaggatttcccgctcaggctggagtt ggctgctgcctcccagacatctgtgtacttctgtgccagcagc SEQ ID NO: 1120 TRBV7-2*03-RIGHT gcttctctgcagagaggactggggaatccgtctccactctgacgatccagcgcacac agcaggaggactcggccgtgtatctctgtaccagcagcttagc SEQ ID NO: 1121 TRBV7-2*04-RIGHT tcgcttctctgcagagaggactgggggatccgtctccactctgacgatccagcgcac acagcaggaggactcggccgtgtatctctgtgccagcagctta SEQ ID NO: 1122 TRBV7-3*04-RIGHT cgatcggttctttgcagtcaggcctgagggatccgtctctactctgaagatccagcg cacagagcggggggactctgccgtgtatctctgtgccagcagc SEQ ID NO: 1123 TRBV7-3*05-RIGHT cgatcggttctttgcagtcaggcctgagggatccgtctctactctgaagatccagcg cacagagcggggggactcagccgtgtatctctgtgccagcagc SEQ ID NO: 1124 TRBV7-4*02-RIGHT aacgagacaaatcagggcggcccagtggtcggttctctgcagagaggcctgagagat cgtctccactccgaagatccagcgcacagagcagggggactca SEQ ID NO: 1125 TRBV7-6*02-RIGHT tgatcggttctctgcagagaggcctgagggatccatctccactctgacgatccagcg cacagagcagcgggactcggccatgtatcgctgtgccagcagc SEQ ID NO: 1126 TRBV7-7*02-RIGHT tgatcggttctctgcagagaggcctgagggatccatctccactctgacgattcagcg cacagagcagcgggactcagccatgtatcgctgtgccagcagc SEQ ID NO: 1127 TRBV7-8*03-RIGHT tcgcttctttgcagaaaggcctgagggatccgtctccactctgaagatccagcgcac acagcaggaggactccgccgtgtatctctgtgccagcagccga SEQ ID NO: 1128 TRBV7-9*02-RIGHT tcggttctctgcagagaggcctaagggatctttctccaccttggagatccagcgcac agagcagggggactcggccatgtatctctgtgccagcagctta SEQ ID NO: 1129 TRBV7-9*04-RIGHT tcggatctctgcagagaggcctaagggatctttctccaccttggagatccagcgcac agagcagggggactcggccatgtatctctgtgccagcagctct SEQ ID NO: 1130 TRBV7-9*05-RIGHT tcggttctctgcagagaggcctaagggatctctctccaccttggagatccagcgcac agagcagggggactcggccatgtatctctgtgccagcaccaaa SEQ ID NO: 1131 TRBV7-9*06-RIGHT tcggttctctgcagagaggcctaagggatctctttccaccttggagatccagcgcac agagcagggggactcggccatgtatctctgtgccagcacgttg SEQ ID NO: 1132 TRBV7-9*07-RIGHT gttctctgcagagaggcctaagggatctttctccaccttggagatccagcgcacaga ggagggggactcggccatgtatctctgtgccagcagcagcagt SEQ ID NO: 1133 TRBV9*03-RIGHT tgaacgattctccgcacaacagttccctgacttgcactctgaactaaacctgagctc tctggagctgggggactcagctttgtatttctgtgccagcagc SEQ ID NO: 1134 TRBV2*02-RIGHT gaagtattatacttacgcaagcacaaggaacaacttgagattgatactgcaaaatct aattgaaaatgactctggggtctattactgtgccacctgggac SEQ ID NO: 1135 TRBV20-1*03-RIGHT gaaggacaagtttctcatcaaccatgcaagcctgaccttgtccactctgacagtgac cagtgcccatcctgaagacagcagcttctacatctgcagtgct SEQ ID NO: 1136 TRGV6*01-RIGHT gcatgatacttatggaagtagaaggataagctggaaatttatacctccaaaactaaa tgaaaatgcctctggggtctattactgtgccacctaggacagg SEQ ID NO: 1137 TRGV4*02-RIGHT gtatgatacttacggaagcacaaggaagaacttgagaatgatactgcgaaatcttat tgaaaatgactctggagtctattactgtgccacctgggatggg SEQ ID NO: 1138 TRGV5P*01-RIGHT gtattatactcatacaccgaggaggtggagctggaatttgagactgcaaaatctaat tgaaaatgattctggggtctattactgtgccacctggggcagg SEQ ID NO: 1139 TRBV10-3*02-RIGHT gctatagtgtctctagatcaaagacagaggatttcctcctcactctggagtccgcta ccagctcccagacatctgtgtacttctgtgccatcagtgagtc SEQ ID NO: 1140 TRBV24/OR9-2*01-RIGHT atacagtgtctctcgacaggcacaggctaaattctccctgtccctagagtctgccat ccccaaccagacagctctttacttctgtgccaccagtgatttg SEQ ID NO: 1141 TRBV20/OR9-2*01-RIGHT acaagtttcccatcaaccatccaaacctgaccttctccgctctgacagtgaccagtg cccatcctgaagacagcagcttctacatctgcagtgctagaga SEQ ID NO: 1142 TRBV11*01-RIGHT ggtaagtaaaaatgctcacacttccacttccactttgaaaataaagttcttagagaa agaagatgaggtggtgtaccactgtgcctgctggattaggcac SEQ ID NO: 1143 TRBV7-8*02-RIGHT gcttctttgcagaaaggcctgagggatccgtctccactctgaagatccagcgcacac agaaggaggactccgccgtgtatctctgtgccagcagcttagc SEQ ID NO: 1144 TRBV7-3*02-RIGHT ggttctttgcagtcaggcctgagggatccgtctctactctgaagatccagcgcacag agcagggggactcagccgtgtatctccgtgccagcagcttaac SEQ ID NO: 1145 TRGV10*01-RIGHT aggcaagaaagaattctcaaactctcacttcaatccttaccatcaagtccgtagaga aagaagacatggccgtttactactgtgctgcgtggtgggtggc SEQ ID NO: 1146 TRGV9*02-RIGHT tgaggtggataggatacctgaaacgtctacatccactctcaccattcacaatgtaga gaaacaggacatagctacctactactgtgccttgtgggaggtg SEQ ID NO: 1147 TRDV3*02-RIGHT gacggttttctgtgaaacacattctgacccagaaagcctttcacttggtgatctctc cagtaaggactgaagacagtgccacttactactgtgcctttag SEQ ID NO: 1148 TRDV2*02-RIGHT aatttccaaggtgacattgatattgcaaagaacctggctgtacttaagatacttgca ccatcagagagagatgaagggtcttactactgtgcctgtgaca SEQ ID NO: 1149 TRGV3*02-RIGHT agtattatactcatacacccaggaggtggagctggatattgagactgcaaaatctaa ttgaaaatgattctggggtctattactgtgccacctgggacag SEQ ID NO: 1150 TRDV2*01-RIGHT tttccaaggtgacattgatattgcaaagaacctggctgtacttaagatacttgcacc atcagagagagatgaagggtcttactactgtgcctgtgacacc SEQ ID NO: 1151 TRBV19*02-RIGHT ggtacagcgtctctcgggagaagaaggaatcctttcctctcactgtgacatcggccc aaaagaacccgacagctttctatctctgtgccagtagtataga SEQ ID NO: 1152 TRAV14/DV4*01-RIGHT actcattgaatttccagaaggcaagaaaatccgccaaccttgtcatctccgcttcac aactgggggactcagcaatgtacttctgtgcaatgagagaggg SEQ ID NO: 1153 TRBV3-2*02-RIGHT gcttctcacctgactctccagacaaagttcatttaaatcttcacatcaattccctgg agcttggtgactctgctgtgtatttctgtgccagcagccaaga SEQ ID NO: 1154 TRGV10*02-RIGHT tggaggcaagaaagaattctcaaactctcacttcaatccttaccatcaagtccgtag agaaagaagacatggccgtttactactgtgctgcgtgggatta SEQ ID NO: 1155 TRAV11*01-RIGHT caaatattttaaagaactgcttggaaaagaaaaattttatagtgtttggaatatcgc agcctctcatctgggagattcagccacctacttctgtgctttg SEQ ID NO: 1156 TRBV-2*01-RIGHT aacttgcctaattgattctcagctcaccacgtccataactattactgagtcaaacac ggagctaggggactcagccctgtatctctgtgccagcaacttg SEQ ID NO: 1157 TRBV8-1*01-RIGHT ggaagggtacaatgtctctggaaacaagctcaagcattttccctcaaccctggagtc tactagcaccagccagacctctgtacctctgtggcagtgcatc SEQ ID NO: 1158 TRAV38-1*01-RIGHT tctctgtgaacttccagaaagcagccaaatccttcagtctcaagatctcagactcac agctgggggacactgcgatgtatttctgtgctttcatgaagca SEQ ID NO: 1159 TRBV22-1*01-RIGHT aggctacgtgtctgccaagaggagaaggggctatttcttctcagggtgaagttggcc cacaccagccaaacagctttgtacttctgtcctgggagcgcac SEQ ID NO: 1160 TRBV16*01-RIGHT gattttcagctaagtgcctcccaaattcaccctgtagccttgagatccaggctacga agcttgaggattcagcagtgtatttttgtgccagcagccaatc SEQ ID NO: 1161 TRBV30*01-RIGHT agaatctctcagcctccagaccccaggaccggcagttcatcctgagttctaagaagc tccttctcagtgactctggcttctatctctgtgcctggagtgt SEQ ID NO: 1162 TRAV3*01-RIGHT tttgaagctgaatttaacaagagccaaacctccttccacctgaagaaaccatctgcc cttgtgagcgactccgctttgtacttctgtgctgtgagagaca SEQ ID NO: 1163 TRAV26-1*01-RIGHT gcctctctgatcatcacagaagacagaaagtccagcaccttgatcctgccccacgct acgctgagagacactgctgtgtactattgcatcgtcagagtcg SEQ ID NO: 1164 TRAV32*01-RIGHT aggctcactgtactgttgaataaaaatgctaaacatgtctccctgcatattacagcc acccaaccaggagactcattcctgtacttctgtgcagtgagaa SEQ ID NO: 1165 TRAV33*01-RIGHT gcaaagcctgtgaactttgaaaaaaagaaaaagttcatcaacctcaccatcaattcc ttaaaactgactcagccaagtacttctgtgctctcaggaatcc SEQ ID NO: 1166 TRBV13*01-RIGHT gattctcagctcaacagttcagtgactatcattctgaactgaacatgagctccttgg agctgggggactcagccctgtacttctgtgccagcagcttagg SEQ ID NO: 1167 TRBV15*01-RIGHT acttccaatccaggaggccgaacacttctttctgctttcttgacatccgctcaccag gcctgggggacacagccatgtacctgtgtgccaccagcagaga SEQ ID NO: 1168 TRAV2*01-RIGHT agggacgatacaacatgacctatgaacggttctcttcatcgctgctcatcctccagg tgcgggaggcagatgctgctgtttactactgtgctgtggagga SEQ ID NO: 1169 TRBV7-1*01-RIGHT ggttctctgcacagaggtctgagggatccatctccactctgaagttccagcgcacac agcagggggacttggctgtgtatctctgtgccagcagctcagc SEQ ID NO: 1170 TRBV23-1*01-RIGHT gattctcatctcaatgccccaagaacgcaccctgcagcctggcaatcctgtcctcag aaccgggagacacggcactgtatctctgcgccagcagtcaatc SEQ ID NO: 1171 TRBV23/OR9-2*01-RIGHT gatgcacaagaagcgattctcatctcaatgccccaagaacccaccctgcagcctggc aatcctgtcctcggaaccgggagacaccgcactgtatctctgt SEQ ID NO: 1172 TRBVA*01-RIGHT tccctattgaaaatatttcctggcaaaaaatagaagttctctttggctctgaaatct gcaactccctttcaggtgtccctgtgtccttgtaccgtcactc SEQ ID NO: 1173 TRBVA/OR9-2*01-RIGHT tccctgttgaaaatatttcccggcaaaaaacagaagttccctttggctctgaaatct gcaaagccctttcagatgtccctgtgtccttgtgccgtcactc SEQ ID NO: 1174 TRBV12-1*01-RIGHT gattctcagcacagatgcctgatgtatcattctccactctgaggatccagcccatgg aacccagggacttgggcctatatttctgtgccagcagctttgc SEQ ID NO: 1175 TRBV26/OR9-2*01-RIGHT ggtatcatgtttcttgaaatactatagcatcttttctcctgaccctgaagtctgcta gcaccaaccagacatgtgtgtatctctgcgccagcagttcatc SEQ ID NO: 1176 TRGV9*01-RIGHT tgaggtggataggatacctgaaacgtctacatccactctcaccattcacaatgtaga gaaacaggacatagctacctactactgtgccttgtgggaggtg SEQ ID NO: 1177 TRGBV*01-RIGHT cttgaggcaagaacaaattttcaaatgtctacttcagtctttaccataaacttcata ggaaaggaagatgaggccatttactactgcactgcttaggacc SEQ ID NO: 1178 TRBV7-3*01-RIGHT ggttctttgcagtcaggcctgagggatccgtctctactctgaagatccagcgcacag agcggggggactcagccgtgtatctctgtgccagcagcttaac SEQ ID NO: 1179 TRBV7-9*01-RIGHT ggttctctgcagagaggcctaagggatctttctccaccttggagatccagcgcacag agcagggggactcggccatgtatctctgtgccagcagcttagc SEQ ID NO: 1180 TRBV7-2*01-RIGHT gcttctctgcagagaggactgggggatccgtctccactctgacgatccagcgcacac agcaggaggactcggccgtgtatctctgtgccagcagcttagc SEQ ID NO: 1181 TRBV7-2*02-RIGHT gcttctctgcagagaggactggggaatccgtctccactctgacgatccagcgcacac agcaggaggactcggccgtgtatctctgtgccagcagcttagc SEQ ID NO: 1182 TRBV7-7*01-RIGHT ggttctctgcagagaggcctgagggatccatctccactctgacgattcagcgcacag agcagcgggactcagccatgtatcgctgtgccagcagcttagc SEQ ID NO: 1183 TRBV7-8*01-RIGHT gcttctttgcagaaaggcctgagggatccgtctccactctgaagatccagcgcacac agcaggaggactccgccgtgtatctctgtgccagcagcttagc SEQ ID NO: 1184 TRBV17*01-RIGHT aacgattcacagctgaaagacctaacggaacgtcttccacgctgaagatccatcccg cagagccgagggactcagccgtgtatctctacagtagcggtgg SEQ ID NO: 1185 TRBV5-8*01-RIGHT agattttcaggtcgccagttccctaattatagctctgagctgaatgtgaacgccttg gagctggaggactcggccctgtatctctgtgccagcagcttgg SEQ ID NO: 1186 TRBV5-7*01-RIGHT caattctcaggtcaccagttccctaactatagctctgagctgaatgtgaacgccttg ttgctaggggactcggccctctatctctgtgccagcagcttgg SEQ ID NO: 1187 TRBV5-6*01-RIGHT cgattctcaggtcaccagttccctaactatagctctgagctgaatgtgaacgccttg ttgctgggggactcggccctctatctctgtgccagcagcttgg SEQ ID NO: 1188 TRBV5-5*01-RIGHT cgattctcagctcgccagttccctaactatagctctgagctgaatgtgaacgccttg ttgctgggggactcggccctgtatctctgtgccagcagcttgg SEQ ID NO: 1189 TRBV5-4*01-RIGHT agattctcaggtctccagttccctaattatagctctgagctgaatgtgaacgccttg gagctggacgactcggccctgtatctctgtgccagcagcttgg SEQ ID NO: 1190 TRBV5-1*01-RIGHT cgattctcagggcgccagttctctaactctcgctctgagatgaatgtgagcaccttg gagctgggggactcggccctttatctttgcgccagcagcttgg SEQ ID NO: 1191 TRBV3-1*01-RIGHT gcttctcacctaaatctccagacaaagctcacttaaatcttcacatcaattccctgg agcttggtgactctgctgtgtatttctgtgccagcagccaaga SEQ ID NO: 1192 TRBV1*01-RIGHT acttcacacctgaatgccctgacagctctcgcttataccttcatgtggtcgcactgc agcaagaagactcagctgcgtatctctgcaccagcagccaaga SEQ ID NO: 1193 TRBV5-3*01-RIGHT cgattctcagggcgccagttccatgactgttgctctgagatgaatgtgagtgccttg gagctgggggactcggccctgtatctctgtgccagaagcttgg SEQ ID NO: 1194 TRBV5-3*02-RIGHT cgattctcagggcgccagttccatgactattgctctgagatgaatgtgagtgccttg gagctgggggactcggccctgtatctctgtgccagaagcttgg SEQ ID NO: 1195 TRBV9*01-RIGHT cgattctccgcacaacagttccctgacttgcactctgaactaaacctgagctctctg gagctgggggactcagctttgtatttctgtgccagcagcgtag SEQ ID NO: 1196 TRBV3-2*01-RIGHT gcttctcacctgactctccagacaaagctcatttaaatcttcacatcaattccctgg agcttggtgactctgctgtgtatttctgtgccagcagccaaga SEQ ID NO: 1197 TRBV2*01-RIGHT aattctcagttgaaaggcctgatggatcaaatttcactctgaagatccggtccacaa agctggaggactcagccatgtacttctgtgccagcagtgaagc SEQ ID NO: 1198 TRBV4-3*01-RIGHT gcttctcacctgaatgccccaacagctctcacttattccttcacctacacaccctgc agccagaagactcggccctgtatctctgcgccagcagccaaga SEQ ID NO: 1199 TRBV4-1*01-RIGHT gcttctcacctgaatgccccaacagctctctcttaaaccttcacctacacgccctgc agccagaagactcagccctgtatctctgcgccagcagccaaga SEQ ID NO: 1200 TRBV4-2*01-RIGHT gcttctcacctgaatgccccaacagctctcacttattccttcacctacacaccctgc agccagaagactcggccctgtatctctgtgccagcagccaaga SEQ ID NO: 1201 TRBV34*01-RIGHT aagataactgccaagttggatgagaaaaagcagcaaagttccctgcatatcacagcc tcccagcccagccatgcaggcatctacctctgtggagcagaca SEQ ID NO: 1202 TRBV28*01-RIGHT ggtacagtgtctctagagagaagaaggagcgcttctccctgattctggagtccgcca gcaccaaccagacatctatgtacctctgtgccagcagtttatg SEQ ID NO: 1203 TRBV20-1*01-RIGHT acaagtttctcatcaaccatgcaagcctgaccttgtccactctgacagtgaccagtg cccatcctgaagacagcagcttctacatctgcagtgctagaga SEQ ID NO: 1204 TRBV20/OR9-2*03-RIGHT acaagtttcccatcaaccatccaaacctgaccttctccgctctgacagtgaccagtg cccatcctgaagacagcagcttctacatctgcagtgctagaga SEQ ID NO: 1205 TRBV6-6*02-RIGHT gaatggctacaacgtctccagatcaaccacagaggatttcccgctcaggctggagtt ggctgctccctcccagacatctgtgtacttctgtgccagcagt SEQ ID NO: 1206 TRBV6-6*01-RIGHT gctacaacgtctccagatcaaccacagaggatttcccgctcaggctggagttggctg ctccctcccagacatctgtgtacttctgtgccagcagttactc SEQ ID NO: 1207 TRBV6-5*01-RIGHT gctacaatgtctccagatcaaccacagaggatttcccgctcaggctgctgtcggctg ctccctcccagacatctgtgtacttctgtgccagcagttactc SEQ ID NO: 1208 TRBV6-8*01-RIGHT gctacaatgtctctagattaaacacagaggatttcccactcaggctggtgtcggctg ctccctcccagacatctgtgtacttgtgtgccagcagttactc SEQ ID NO: 1209 TRBV6-9*01-RIGHT gctacaatgtatccagatcaaacacagaggatttcccgctcaggctggagtcagctg ctccctcccagacatctgtatacttctgtgccagcagttattc SEQ ID NO: 1210 TRBV6-7*01-RIGHT gctacaatgtctccagatcaaacacagaggatttccccctcaagctggagtcagctg ctccctctcagacttctgtttacttctgtgccagcagttactc SEQ ID NO: 1211 TRBV12-3*01-RIGHT gattctcagctaagatgcctaatgcatcattctccactctgaagatccagccctcag aacccagggactcagctgtgtacttctgtgccagcagtttagc SEQ ID NO: 1212 TRBV12-4*01-RIGHT gattctcagctaagatgcctaatgcatcattctccactctgaagatccagccctcag aacccagggactcagctgtgtacttctgtgccagcagtttagc SEQ ID NO: 1213 TRBV12-5*01-RIGHT gattctcagcagagatgcctgatgcaactttagccactctgaagatccagccctcag aacccagggactcagctgtgtatttttgtgctagtggtttggt SEQ ID NO: 1214 TRBV12-2*01-RIGHT gattctcagctgagaggcctgatggatcattctctactctgaagatccagcctgcag agcagggggactcggccgtgtatgtctgtgcaagtcgcttagc SEQ ID NO: 1215 TRBV6-1*01-RIGHT gctacaatgtctccagattaaacaaacgggagttctcgctcaggctggagtcggctg ctccctcccagacatctgtgtacttctgtgccagcagtgaagc SEQ ID NO: 1216 TRBV7-4*01-RIGHT ggttctctgcagagaggcctgagagatccgtctccactctgaagatccagcgcacag agcagggggactcagctgtgtatctctgtgccagcagcttagc SEQ ID NO: 1217 TRBV7-5*01-RIGHT tcaattctccacagagaggtctgaggatctttctccacctgaagatccagcgcacag agcaagggcgactcggctgtgtatctctgtgccagaagcttag SEQ ID NO: 1218 TRBV20*01-RIGHT aaagaaaggctaaaagccacattaacaaagaaggaaagctttctgcacatcacagcc cctaaacctgaagactcagccacttatctctgtgctgtgcagg SEQ ID NO: 1219 TRBV11-1*01-RIGHT gattttctgcagagaggctcaaaggagtagactccactctcaagatccagcctgcag agcttggggactcggccatgtatctctgtgccagcagcttagc SEQ ID NO: 1220 TRBV15*01-RIGHT acattttaaagaagcgcttggaaaagagaagttttatagtgttttgaatatgctggt ctctcatcctggagattcaggcacctacttctgtgctttgagg SEQ ID NO: 1221 TRBV7*01-RIGHT aaaggaagactaaatgctacattactgaagaatggaagcagcttgtacattacagcc gtgcagcctgaagattcagccacctatttctgtgctgtagatg SEQ ID NO: 1222 TRAV163*01-RIGHT gcttcactgctgaccttaacaaaggcgagacatctttccacctgaagaaaccatttg ctcaagaggaagactcagccatgtattactgtgctctaagtgg SEQ ID NO: 1223 TRAV6*01-RIGHT agactgaaggtcacctttgataccacccttaaacagagtttgtttcatatcacagcc tcccagcctgcagactcagctacctacctctgtgctctagaca SEQ ID NO: 1224 TRBV19*01-RIGHT ggtacagcgtctctcgggagaagaaggaatcctttcctctcactgtgacatcggccc aaaagaacccgacagctttctatctctgtgccagtagtataga SEQ ID NO: 1225 TRAV14/DV4*02-RIGHT actcattgaatttccagaaggcaagaaaatccgccaaccttgtcatctccgcttcac aactgggggactcagcaatgtatttctgtgcaatgagagaggg SEQ ID NO: 1226 TRAV9-1*01-RIGHT gttttgaagccatgtaccgtaaagaaaccacttctttccacttggagaaagactcag ttcaagagtcagactccgctgtgtacttctgtgctctgagtga SEQ ID NO: 1227 TRAV9-2*01-RIGHT gttttgaagccacataccgtaaagaaaccacttctttccacttggagaaaggctcag ttcaagtgtcagactcagcggtgtacttctgtgctctgagtga SEQ ID NO: 1228 TRAV1-1*01-RIGHT gtttttcttcattccttagtcgctctgatagttatggttacctccttctacaggagc tccagatgaaagactctgcctcttacttctgcgctgtgagaga SEQ ID NO: 1229 TRAV38-8*01-RIGHT ttctctgtgaacttccagaaagcagccaaatccttcagtctcaagatctcagactca cagctgggggatgccgcgatgtatttctgtgcttataggagcg SEQ ID NO: 1230 TRAV19*01-RIGHT attcttggaacttccagaaatccaccagttccttcaacttcaccatcacagcctcac aagtcgtggactcagcagtatacttctgtgctctgagtgaggc SEQ ID NO: 1231 TRAV30*01-RIGHT aaaatatctgcttcatttaatgaaaaaaagcagcaaagctccctgtaccttacggcc tcccagctcagttactcaggaacctacttctgcggcacagaga SEQ ID NO: 1232 TRGV7*01-RIGHT aaagtatgacactggaagcacaaggagcaattggaatttgagactgcaaaatctaat taaaaatgattctgggttctattactgtgccacctgggacagg SEQ ID NO: 1233 TRGV7*01-RIGHT aaagtatgacactggaagcacaaggagcaattggaatttgagactgcaaaatctaat taaaaatgattctgggttctattactgtgccacctgggacagg SEQ ID NO: 1234 TRGV3*01-RIGHT gtattatactcatacacccaggaggtggagctggatattgagactgcaaaatctaat tgaaaatgattctggggtctattactgtgccacctgggacagg SEQ ID NO: 1235 TRGV5*01-RIGHT gtattatactcatacacccaggaggtggagctggatattgatactacgaaatctaat tgaaaatgattctggggtctattactgtgccacctgggacagg SEQ ID NO: 1236 TRGV8*01-RIGHT gtatcatacttatgcaagcacagggaagagccttaaatttatactggaaaatctaat tgaacgtgactctggggtctattactgtgccacctgggatagg SEQ ID NO: 1237 TRGV4*01-RIGHT gtatgatacttatggaagcacaaggaagaacttgagaatgatactgcgaaatcttat tgaaaatgactctggagtctattactgtgccacctgggatggg SEQ ID NO: 1238 TRGV2*01-RIGHT gtattatacttacgcaagcacaaggaacaacttgagattgatactgcgaaatctaat tgaaaatgactctggggtctattactgtgccacctgggacggg SEQ ID NO: 1239 TRGV5P*02-RIGHT gtattatactcatacaccgaggaggtggagctggaatttgagactgcaaaatctaat tgaaaatgattctggggtctattactgtgccacctggggcagg SEQ ID NO: 1240 TRAV21*01-RIGHT aagacttaatgcctcgctggataaatcatcaggacgtagtactttatacattgcagc ttctcagcctggtgactcagccacctacctctgtgctgtgagg SEQ ID NO: 1241 TRBV29/OR9-2*01-RIGHT acaagtttcccatcagccgcccaaacctaacattctcaactctgactgtgagcaaca ggagacctgaagacagcagcatatacctctgcagcgttgaaga SEQ ID NO: 1242 TRAV37*01-RIGHT agattcacagccaggcttaaaaaaggagaccagcacatttccctgcacatacaggat tcccagctccatgactcaaccacattcttctgcgcagcaagca SEQ ID NO: 1243 TRBV21/OR9-2*01-RIGHT gattttcagcccaatgcccccaaaactcaccctgtaccttggagatccagtccacgg agtcaggagacacagcacggtatttctgtgccaacagcaaagc SEQ ID NO: 1244 TRBV21-1*01-RIGHT gatttttagcccaatgctccaaaaactcatcctgtaccttggagatccagtccacgg agtcaggggacacagcactgtatttctgtgccagcagcaaagc SEQ ID NO: 1245 TRAV8-6*01-RIGHT gttttgaggctgaatttaacaagagtcaaacttccttccacttgaggaaaccctcag tccatataagcgacacggctgagtacttctgtgctgtgagtga SEQ ID NO: 1246 TRAV8-3*01-RIGHT gctttgaggctgaatttaagaggagtcaatcttccttcaatctgaggaaaccctctg tgcattggagtgatgctgctgagtacttctgtgctgtgggtgc SEQ ID NO: 1247 TRBV29-1*01-RIGHT acaagtttcccatcagccgcccaaacctaacattctcaactctgactgtgagcaaca tgagccctgaagacagcagcatatatctctgcagcgttgaaga SEQ ID NO: 1248 TRBV25/OR9-2*01-RIGHT agtcaacagtctccagaataaggatagagcgttttcccctgaccctggagtctgcca gcccctcacatacctctcagtacctctgtgccagcagtgaata SEQ ID NO: 1249 TRBV25-1*01-RIGHT agtcaacagtctccagaataaggacggagcattttcccctgaccctggagtctgcca ggccctcacatacctctcagtacctctgtgccagcagtgaata SEQ ID NO: 1250 TRAV35*01-RIGHT aagactgactgctcagtttggtataaccagaaaggacagcttcctgaatatctcagc atccatacctagtgatgtaggcatctacttctgtgctgggcag SEQ ID NO: 1251 TRAV25*01-RIGHT gaaaagactgacatttcagtttggagaagcaaaaaagaacagctccctgcacatcac agccacccagactacagatgtaggaacctacttctgtgcaggg SEQ ID NO: 1252 TRAV12-2*01-RIGHT aggtttacagcacagctcaataaagccagccagtatgtttctctgctcatcagagac tcccagcccagtgattcagccacctacctctgtgccgtgaaca SEQ ID NO: 1253 TRAV12-1*01-RIGHT aggtttacagcacagctcaatagagccagccagtatatttccctgctcatcagagac tccaagctcagtgattcagccacctacctctgtgtggtgaaca SEQ ID NO: 1254 TRAV12-3*01-RIGHT aggtttacagcacaggtcgataaatccagcaagtatatctccttgttcatcagagac tcacagcccagtgattcagccacctacctctgtgcaatgagcg SEQ ID NO: 1255 TRAV23/DV6*01-RIGHT agattcacaatctccttcaataaaagtgccaagcagttctcattgcatatcatggat tcccagcctggagactcagccacctacttctgtgcagcaagca SEQ ID NO: 1256 TRAV22*01-RIGHT agattaagcgccacgactgtcgctacggaacgctacagcttattgtacatttcctct tcccagaccacagactcaggcgtttatttctgtgctgtggagc SEQ ID NO: 1257 TRAV41*01-RIGHT aagattaattgccacaataaacatacaggaaaagcacagctccctgcacatcacagc ctcccatcccagagactctgccgtctacatctgtgctgtcaga SEQ ID NO: 1258 TRAV39*01-RIGHT cgattaatggcctcacttgataccaaagcccgtctcagcaccctccacatcacagct gccgtgcatgacctctctgccacctacttctgtgccgtggaca SEQ ID NO: 1259 TRAV36/DV7*01-RIGHT agactaagtagcatattagataagaaagaactttccagcatcctgaacatcacagcc acccagaccggagactcggccatctacctctgtgctgtggagg SEQ ID NO: 1260 TRAV29/DV5*01-RIGHT agattcactgtcttcttaaacaaaagtgccaagcacctctctctgcacattgtgccc tcccagcctggagactctgcagtgtacttctgtgcagcaagcg SEQ ID NO: 1261 TRAV27*01-RIGHT aagagactaacctttcagtttggtgatgcaagaaaggacagttctctccacatcact gcagcccagcctggtgatacaggcctctacctctgtgcaggag SEQ ID NO: 1262 TRBV6-4*01-RIGHT gttatagtgtctccagagcaaacacagatgatttccccctcacgttggcgtctgctg taccctctcagacatctgtgtacttctgtgccagcagtgactc SEQ ID NO: 1263 TRBV10-1*01-RIGHT gctacagtgtctctagatcaaacacagaggacctccccctcactctggagtctgctg cctcctcccagacatctgtatatttctgcgccagcagtgagtc SEQ ID NO: 1264 TRBV10-2*01-RIGHT gctatgttgtctccagatccaagacagagaatttccccctcactctggagtcagcta cccgctcccagacatctgtgtatttctgcgccagcagtgagtc SEQ ID NO: 1265 TRBV6-2*01-RIGHT gctacaatgtctccagattaaaaaaacagaatttcctgctggggttggagtcggctg ctccctcccaaacatctgtgtacttctgtgccagcagttactc SEQ ID NO: 1266 TRBV10-3*01-RIGHT gctatagtgtctctagatcaaagacagaggatttcctcctcactctggagtccgcta ccagctcccagacatctgtgtacttctgtgccatcagtgagtc SEQ ID NO: 1267 TRAV24*01-RIGHT ggacgaataagtgccactcttaataccaaggagggttacagctatttgtacatcaaa ggatcccagcctgaagactcagccacatacctctgtgccttta SEQ ID NO: 1268 TRBV14*01-RIGHT gattcttagctgaaaggactggagggacgtattctactctgaaggtgcagcctgcag aactggaggattctggagtttatttctgtgccagcagccaaga SEQ ID NO: 1269 TRBV24-1*01-RIGHT atacagtgtctctcgacaggcacaggctaaattctccctgtccctagagtctgccat ccccaaccagacagctctttacttctgtgccaccagtgatttg SEQ ID NO: 1270 TRBV24/OR9-2*03-RIGHT agtgtctcttgacaggaacaggctaaattctccctgtccctagagcctgccaccccc aaccagacagcttctaggttacttcagtgccaccagtgatttc SEQ ID NO: 1271 TRAV8-2*01-RIGHT gttttgaggctgaatttaagaagagtgaaacctccttccacctgacgaaaccctcag cccatatgagcgacgcggctgagtacttctgtgttgtgagtga SEQ ID NO: 1272 TRAV8-4*01-RIGHT gttttgaggctgaatttaagaagagtgaaacctccttccacctgacgaaaccctcag cccatatgagcgacgcggctgagtacttctgtgctgtgagtga SEQ ID NO: 1273 TRBV22/OR9-2*01-RIGHT ggctacggtgtctcccgagaggagaaggggctgtttcttctcatggtgaagctggcc cacaccagccaaacagctctgtacttctgtcctgggagtgcac SEQ ID NO: 1274 TRAV26-2*01-RIGHT ggcctctctggcaatcgctgaagacagaaagtccagtaccttgatcctgcaccgtgc taccttgagagatgctgctgtgtactactgcatcctgagagac SEQ ID NO: 1275 TRBV11-2*01-RIGHT gattttctgcagagaggctcaaaggagtagactccactctcaagatccagcctgcaa agcttgaggactcggccgtgtatctctgtgccagcagcttaga SEQ ID NO: 1276 TRBV11-3*01-RIGHT gattttctgcagagaggctcaaaggagtagactccactctcaagatccagcctgcag agcttggggactcggccgtgtatctctgtgccagcagcttaga SEQ ID NO: 1277 TRAV8-1*01-RIGHT gctttgaggctgaatttataaagagtaaattctcctttaatctgaggaaaccctctg tgcagtggagtgacacagctgagtacttctgtgccgtgaatgc SEQ ID NO: 1278 TRBV7-5*02-RIGHT caattctccacagagaggtctgaggatctttctccacctgaagatccagcgcacaga gcaagggcgactcggctgtgtatctctgtgtcagaagcttagc SEQ ID NO: 1279 TRBV7-6*01-RIGHT ggttctctgcagagaggcctgagggatccatctccactctgacgatccagcgcacag agcagcgggactcggccatgtatcgctgtgccagcagcttagc SEQ ID NO: 1280 TRGV11*02-RIGHT gataagtaaaaatgctcacacttccacttccactttgaaaataaagttcttagagaa agaagatgaggtggtgtaccactgtgcctgctggattaggcac SEQ ID NO: 1281 TRAV17*01-RIGHT agattaagagtcacgcttgacacttccaagaaaagcagttccttgttgatcacggct tcccgggcagcagacactgcttcttacttctgtgctacggacg SEQ ID NO: 1282 TRBV27*01-RIGHT ggtacaaagtctctcgaaaagagaagaggaatttccccctgatcctggagtcgccca gccccaaccagacctctctgtacttctgtgccagcagtttatc SEQ ID NO: 1283 TRDV1*01-RIGHT attctgtcaacttcaagaaagcagcgaaatccgtcgccttaaccatttcagccttac agctagaagattcagcaaagtacttttgtgctcttggggaact SEQ ID NO: 1284 TRBV18*01-RIGHT gattttctgctgaatttcccaaagagggccccagcatcctgaggatccagcaggtag tgcgaggagattcggcagcttatttctgtgccagctcaccacc SEQ ID NO: 1285 TRAV5*01-RIGHT agactcactgttctattgaataaaaaggataaacatctgtctctgcgcattgcagac acccagactggggactcagctatctacttctgtgcagagagta SEQ ID NO: 1286 TRAV13-2*01-RIGHT agagtcaccgttttattgaataagacagtgaaacatctctctctgcaaattgcagct actcaacctggagactcagctgtctacttttgtgcagagaata SEQ ID NO: 1287 TRDV2*03-RIGHT tttccaaggtgacattgatattgcaaagaacctggctgtacttaagatacttgcacc atcagagagagatgaagggtcttactactgtgcctgtgacacc SEQ ID NO: 1288 TRAV1-2*01-RIGHT gtttttcttcattccttagtcggtctaaagggtacagttacctccttttgaaggagc tccagatgaaagactctgcctcttacctctgtgctgtgagaga SEQ ID NO: 1289 TRDV3*01-RIGHT gacggttttctgtgaaacacattctgacccagaaagcctttcacttggtgatctctc cagtaaggactgaagacagtgccacttactactgtgcctttag SEQ ID NO: 1290 TRAV31*01-RIGHT tattctgtgagcttccagaaaacaactaaaactattcagcttatcatatcatcatca cagccagaagacctgcaacatatttctgttgtctcaaagagcc SEQ ID NO: 1291 TRAV10*01-RIGHT agatatacagcaactctggatgcagacacaaagcaaagctctctgcacatcacagcc tcccagctcagcgattcagcctcctacatctgtgtggtgagcg SEQ ID NO: 1292 TRAV28*01-RIGHT gaagactaaaatccgcagtcaaagctgaggaactttatggccacctatacatcagat tcccagcctgaggactcagctatttacttctgtgctgtgggga SEQ ID NO: 1293 TRAV40*01-RIGHT aaaacttcggaggcggaaatattaaagacaaaaactcccccattgtgaaatattcag tccaggtatcagactcagccgtgtactactgtcttctgggaga SEQ ID NO: 1294 TRGV6*02-RIGHT gcatgatacttatggaagtagaaggataagctggaaatttatacctccaaaactaaa tgaaaatgcctctggggtctattactgtgccacctaggacagg SEQ ID NO: 1295 TRAV18*01-RIGHT gttttcaggccagtcctatcaagagtgacagttccttccacctggagaagccctcgg tgcagctgtcggactctgccgtgtactactgcgctctgagaga SEQ ID NO: 1296 TRBV26*01-RIGHT ggtatcatgtttcttgaaatactatagcatcttttcccctgaccctgaagtctgcca gcaccaaccagacatctgtgtatctctatgccagcagttcatc SEQ ID NO: 1297 TRBV8-2*01-RIGHT agaggggtactgtgtttcttgaaacaagcttgagcatttccccaatcctggcatcca ccagcaccagccagacctatctgtaccactgtggcagcacatc SEQ ID NO: 1298 TRGVA*01-RIGHT agataaaatcatagccaaggatggcagcagctctatcttggcagtactgaagttgga gacaggcatcgagggcatgaactactgcacaacctgggccctg SEQ ID NO: 1299 TRAV4*01-RIGHT gcctccctgtttatccctgccgacagaaagtccagcactctgagcctgccccgggtt tccctgagcgacactgctgtgtactactgcctcgtgggtgaca SEQ ID NO: 1300 TRAV8-7*01-RIGHT aggctgaatttaagaagagcgaaacctccttctacctgaggaaaccatcaacccatg tgagtgatgctgctgagtacttctgtgctgtgggtgacaggag SEQ ID NO: 1301 TRAV13-1*01-RIGHT cgaattgctgttacattgaacaagacagccaaacatttctccctgcacatcacagag acccaacctgaagactcggctgtctacttctgtgcagcaagta SEQ ID NO: 1302 TRBVB*01-RIGHT gactctgagaccctctgcagcagcagcctatcagtgcagccacatcctctctgagcg gatatgacaaaccccagggttgaagcgacctaacctatgagcc SEQ ID NO: 1303 TRAV8-5*01-RIGHT tggacacttatcacttccccaatcaatacccctgtgatttcctatgcctgtctttac tttaatctcttaatcctgtcagctgaggaggatgtatgtcacc SEQ ID NO: 1304 TRBV16*02-RIGHT gattttcagctaagtgcctcccaaattcaccctgtagccttgagatccaggctacga agcttgaggattcagcagtgtatttttgtgccagcagccaatc SEQ ID NO: 1305 TRBV26/OR9-2*02-RIGHT ggtatcatgtttcttgaaatactatagcatcttttctcctgaccctgaagtctgcta gcaccaaccagacatgtgtgtatctctgcgccagcagttcatc SEQ ID NO: 1306 TRBV7-3*03-RIGHT ggttctttgcagtcaggcctgagggatccgtctctactctgaagatccagcgcacag agcagggggactcagccgcgtatctccgtgccagcagcttaac SEQ ID NO: 1307 TRBV7-9*03-RIGHT tgatcggttctctgcagagaggcctaagggatctttctccaccttggagatccagcg cacagagcagggggactcggccatgtatctctgtgccagcagc SEQ ID NO: 1308 TRBV9*02-RIGHT cgattctccgcacaacagttccctgacttgcactctgaactaaacctgagctctctg gagctgggggactcagctttgtatttctgtgccagcagcgtag SEQ ID NO: 1309 TRBV29/OR9-2*02-RIGHT acaagtttcccatcagccgcccaaacctaacattctcaactctgactgtgagcaaca ggagacctgaagacagcagcatatacctctgcagcgttgaaga SEQ ID NO: 1310 TRAV8-6*02-RIGHT gttttgaggctgaatttaacaagagtcaaacttccttccacttgaggaaaccctcag tccatataagcgacacggctgagtacttctgtgctgtgagtga SEQ ID NO: 1311 TRBV6-4*02-RIGHT gttatagtgtctccagagcaaacacagatgatttccccctcacgttggcgtctgctg taccctctcagacatctgtgtacttctgtgccagcagtgactc SEQ ID NO: 1312 TRBV10-1*02-RIGHT agatggctacagtgtctctagatcaaacacagaggacctccccctcactctggagtc tgctgcctcctcccagacatctgtatatttctgcgccagcagt SEQ ID NO: 1313 TRBV6-3*01-RIGHT gctacaatgtctccagattaaaaaaacagaatttcctgctggggttggagtcggctg ctccctcccaaacatctgtgtacttctgtgccagcagttactc SEQ ID NO: 1314 TRAJ1*01 aatagagacacggggcatggtatgaaagtattacctcccagttgcaatttggcaaag gaaccagagtttccacttctccccgtacgtctgcccatgccca SEQ ID NO: 1315 TRAJ10*01 gaggcatcaaacactgtgatactcacgggaggaggaaacaaactcacctttgggaca ggcactcagctaaaagtggaactcagtaagtatgagattctat SEQ ID NO: 1316 TRAJ11*01 tatggggatttgctatagtgtgaattcaggatacagcaccctcacctttgggaaggg gactatgcttctagtctctccaggtacatgttgaccccatccc SEQ ID NO: 1317 TRAJ12*01 actgactaagaaacactgtgggatggatagcagctataaattgatcttcgggagtgg gaccagactgctggtcaggcctggtaagtaaggtgtcagagag SEQ ID NO: 1318 TRAJ13*01 aaggcaggcattacagtgtgaattctgggggttaccagaaagttacctttggaattg gaacaaagctccaagtcatcccaagtgagtccaatttcctatg SEQ ID NO: 1319 TRAJ13*02 aaaggcaggcattacagtgtgaattctgggggttaccagaaagttacctttggaact ggaacaaagctccaagtcatcccaagtgagtccaatttcctat SEQ ID NO: 1320 TRAJ14*01 tttgtcaggcagcacagtgctgtgatttatagcacattcatctttgggagtgggaca agattatcagtaaaacctggtaagtaggcaatatgtcactaaa SEQ ID NO: 1321 TRAJ15*01 cagggcctcatttcactgtgccaaccaggcaggaactgctctgatctttgggaaggg aaccaccttatcagtgagttccagtaagtacctgataattatt SEQ ID NO: 1322 TRAJ15*02 cagggcctcatttcactgtgccaaccaggcaggaactgctctgatctttgggaaggg aacccacctatcagtgagttccagtaagtacctgataattatt SEQ ID NO: 1323 TRAJ16*01 tggtacaatagatcactgtgggttttcagatggccagaagctgctctttgcaagggg aaccatgttaaaggtggatcttagtaagtattattactaatga SEQ ID NO: 1324 TRAJ17*01 cctgtggtttttgctgggccttaaatcattgtgtgatcaaagctgcaggcaacaagc taacttttggaggaggaaccagggtgctagttaaaccaagtga SEQ ID NO: 1325 TRAJ18*01 aggggaccagcattgtgccgacagaggctcaaccctggggaggctatactttggaag aggaactcagttgactgtctggcctggtgagtgagtcgctttc SEQ ID NO: 1326 TRAJ2*01 ttttgcagaggacagatgtggctatcaaagattttacaatttcacctttggaaaggg atccaaacataatgtcactccaagtaagtgagcagccttttgt SEQ ID NO: 1327 TRAJ20*01 tggtgtcacctacggtatgaatactggaggaacaattgataaactcacatttgggaa agggacccatgtattcattatatctggtgagtcatcccaggtg SEQ ID NO: 1328 TRAJ20*01 tgtaggcgacctcgcactgtggttctaacgactacaagctcagctttggagccggaa ccacagtaactgtaagagcaagtaagtaagaaagaaaagtcca SEQ ID NO: 1329 TRAJ21*01 tgtaatgccaataaacatggtgtacaacttcaacaaattttactttggatctgggac caaactcaatgtaaaaccaagtaagttatagttgcctagaaga SEQ ID NO: 1330 TRAJ22*01 gttgagcaaatcatagtgtttcttctggttctgcaaggcaactgacctttggatctg ggacacaattgactgttttacctggtaggctgcctcaattaaa SEQ ID NO: 1331 TRAJ23*01 aggatatgtaacacagtgtgatttataaccagggaggaaagcttatcttcggacagg gaacggagttatctgtgaaacccagtaagtataaaattgtatc SEQ ID NO: 1332 TRAJ23*02 gactggatgtgtttttgacaggatatgtaacacagtgtgatttataaccagggagga aagcttatcttcggacagggaacggagctatctgtgaaaccca SEQ ID NO: 1333 TRAJ24*01 gaggtgtttgtcacagtgtgacaactgacagctgggggaaattcgagtttggagcag ggacccaggttgtggtcaccccaggtaagcccattcctggagc SEQ ID NO: 1334 TRAJ24*02 gaggtgtttgtcacagtgtgacaactgacagctgggggaaattgcagtttggagcag ggacccaggttgtggtcaccccaggtaagccccattccctgga SEQ ID NO: 1335 TRAJ25*01 atgctgagataatcactatgcagaaggacaaggcttctcctttatctttgggaaggg gacaaggctgcttgtcaagccaagtaagtgacatataatttat SEQ ID NO: 1336 TRAJ26*01 ctgagcccagaaacactgtggggataactatggtcagaattttgtctttggtcccgg aaccagattgtccgtgctgccctgtaagtacagttaagtggag SEQ ID NO: 1337 TRAJ27*02 caatagcactaaagactgtgtaacaccaatgcaggcaaatcaacctttggggatggg actacgctcactgtgaagccaagtaagttgtgttcttctttgc SEQ ID NO: 1338 TRAJ28*01 agaaaggaaactctgtgcatactctggggctgggagttaccaactcactttcgggaa ggggaccaaactctcggtcataccaagtaagttcttctttctg SEQ ID NO: 1339 TRAJ29*01 ttatggaggaaatcactgtgggaattcaggaaacacacctcttgtctttggaaaggg cacaagactttctgtgattgcaagtaagtgtttctagccatcc SEQ ID NO: 1340 TRAJ3*01 aaagaccttacccacagtgggggtacagcagtgcttccaagataatctttggatcag ggaccagactcagcatccggccaagtaagtagaatgaagcagg SEQ ID NO: 1341 TRAJ30*01 gttatggtcccaatcacagtgtgaacagagatgacaagatcatctttggaaaaggga cacgacttcatattctccccagtaagtgctgtttatgtgattt SEQ ID NO: 1342 TRAJ31*01 agtaaaggcaggaagtgctgtggaataacaatgccagactcatgtttggagatggaa ctcagctggtggtgaagcccagtaagtggccatgttttattga SEQ ID NO: 1343 TRAJ32*01 ggctctgaaggactgtgtgaattatggcggtgctacaaacaagctcatctttggaac tggcactctgcttgctgtccagccaagtacgtaagtagtggca SEQ ID NO: 1344 TRAJ32*02 gtgattcagccacctacctctgtgccgatggtggtgctacaaacaagctcatctttg gaactggcactctgcttgctgtccagccaaatatccagaaccc SEQ ID NO: 1345 TRAJ33*01 gttaaggtttttgtgtctgtgtggatagcaactatcagttaatctggggcgctggga ccaagctaattataaagccaggtaagtctcagagatgtgactg SEQ ID NO: 1346 TRAJ34*01 aggtttttgtagatctcagtatcactgtgtcttataacaccgacaagctcatctttg ggactgggaccagattacaagtctttccaagt SEQ ID NO: 1347 TRAJ35*01 taaaagaatgagccattgtggataggctttgggaatgtgctgcattgcgggtccggc actcaagtgattgttttaccacgtaagtatatcttttctcatt SEQ ID NO: 1348 TRAJ36*01 tactgggcagaaacactgtgtcaaactggggcaaacaacctcttctttgggactgga acgagactcaccgttattccctgtaagtccttacctcttgaca SEQ ID NO: 1349 TRAJ37*01 aaagtacagcattagagtgtggctctggcaacacaggcaaactaatctttgggcaag ggacaactttacaagtaaaaccaggtaggtctggatgtttcca SEQ ID NO: 1350 TRAJ37*02 ctcagcggtgtacttctgtgctcttcatggctctagcaacacaggcaaactaatctt tgggcaagggacaactttacaagtaaaaccagatatccagaac SEQ ID NO: 1351 TRAJ38*01 aaagctttctatgactgtgtaatgctggcaacaaccgtaagctgatttggggattgg gaacaagcctggcagtaaatccgagtgagtcttcgtgttaact SEQ ID NO: 1352 TRAJ39*02 cagccgaagatcactgtgtgaataataatgcaggcaacatgctcacctttggagggg gaacaaggttaatggtcaaaccccgtgagtatctctgctgaat SEQ ID NO: 1353 TRAJ4*01 aagcaccatctgattgtgtgttttctggtggctacaataagctgatttttggagcag ggaccaggctggctgtacacccatgtgagtatgaccctgcaag SEQ ID NO: 1354 TRAJ40*01 tatgttggtttatgtagagacacataacactgtgactacctcaggaacctacaaata catctttggaacaggcaccaggctgaaggttttagcaagt SEQ ID NO: 1355 TRAJ41*01 ttagggagaacgcactgtggaactcaaattccgggtatgcactcaacttcggcaaag gcacctcgctgttggtcacaccccgtgagtttttgtggtttac SEQ ID NO: 1356 TRAJ42*01 agccccataggactgtgtgaattatggaggaagccaaggaaatctcatctttggaaa aggcactaaactctctgttaaaccaagtaagtgttggggattc SEQ ID NO: 1357 TRAJ43*01 ttgttagagcatgtattactgtgacaataacaatgacatgcgctttggagcagggac cagactgacagtaaaaccaagtaagttgggggaatgggtcaat SEQ ID NO: 1358 TRAJ44*01 aggtttctgttatgaagcatctcacagtgtaaataccggcactgccagtaaactcac ctttgggactggaacaagacttcaggtcacgctcggt SEQ ID NO: 1359 TRAJ45*01 agggttggcccagagtgtgtattcaggaggaggtgctgacggactcacctttggcaa agggactcatctaatcatccagccctgtaagtgcttttgcctg SEQ ID NO: 1360 TRAJ46*01 aagctgctgacagccgtgagaagaaaagcagcggagacaagctgacttttgggaccg ggactcgtttagcagttaggcccagtaagtctgagcagaaagt SEQ ID NO: 1361 TRAJ47*01 gtagaggagtttgacgctgtgtggaatatggaaacaaactggtctttggcgcaggaa ccattctgagagtcaagtcctgtgagtataaaacacactcaag SEQ ID NO: 1362 TRAJ47*02 gtgtactattgcatctcggccctggaatatggaaacaagctggtctttggcgcagga accattctgagagtcaagtcctatatccagaaccctgaccctg SEQ ID NO: 1363 TRAJ48*01 atgacttagaacactgtgtatctaactttggaaatgagaaattaacctttgggactg gaacaagactcaccatcatacccagtaagttcttcatccttgg SEQ ID NO: 1364 TRAJ49*01 tgttgagcttcctatcacagtggaacaccggtaaccagttctattttgggacaggga caagtttgacggtcattccaagtaagtcaaagaaaattttcca SEQ ID NO: 1365 TRAJ5*01 tactgtgatgtaccagggtgtggacacgggcaggagagcacttacttttgggagtgg aacaagactccaagtgcaaccaagtaagtacccaaacttaggc SEQ ID NO: 1366 TRAJ50*01 taaaggtttggatggctgtgtgaaaacctcctacgacaaggtgatatttgggccagg gacaagcttatcagtcattccaagtaagtgtccctggggtgct SEQ ID NO: 1367 TRAJ51*01 aaactccctgaagcagggagatgcgtgacagctatgagaagctgatatttggaaagg agacatgactaactgtgaagccaagcaagctggaaagacctaa SEQ ID NO: 1368 TRAJ52*01 gcctccagtgcagtgctaatgctggtggtactagctatggaaagctgacatttggac aagggaccatcttgactgtccatccaagtaagtgtaacaagac SEQ ID NO: 1369 TRAJ53*01 agccttctgtggctgtgagaatagtggaggtagcaactataaactgacatttggaaa aggaactctcttaaccgtgaatccaagtaagtttgaagggagt SEQ ID NO: 1370 TRAJ54*01 taaagcctcgtgctgtggtgtaattcagggagcccagaagctggtatttggccaagg aaccaggctgactatcaacccaagtaagtatgacagggtgaag SEQ ID NO: 1371 TRAJ55*01 gaggatggatccctgttagtgacaagtgctggtaatgctcctgttggggaaagggga tgagtacaaaaataaatccaagtaagtgtggagggacaagaag SEQ ID NO: 1372 TRAJ56*01 agatcctcgtgtcattgtgttatactggagccaatagtaagctgacatttggaaaag gaataactctgagtgttagaccaggtatgttttaatgaatgtt SEQ ID NO: 1373 TRAJ57*01 aagcagtctgtgggggtgtaactcagggcggatctgaaaagctggtctttggaaagg gaacgaaactgacagtaaacccatgtaagtctgaataatgctt SEQ ID NO: 1374 TRAJ58*01 aagcccctcagcacagtgtttaagaaaccagtggctctaggttgacctttggggaag gaacacagctcacagtgaatcctggtaagtggaggggagcatt SEQ ID NO: 1375 TRAJ59*01 atgtaaaggcagcagctcctgtgggaaggaaggaaacaggaaatttacatttggaat ggggacgcaagtgagagtgaagctatctttaaaccaaaggtgt SEQ ID NO: 1376 TRAJ6*01 caggttttatcaaaggctgtcctcactgtgtgcatcaggaggaagctacatacctac atttggaagaggaaccagccttattgttcatccgtgtaagt SEQ ID NO: 1377 TRAJ60*01 gtaaagggcctgggcactatgtgaagatcacctagatgctcaactttgggaagggga ctgagttaattgtgagcctgggtgagtacctcaactccagagg SEQ ID NO: 1378 TRAJ61*01 taaaggtgcccactcctgtgggtaccgggttaataggaaactgacatttggagccaa cactagaggaatcatgaaactcagcaagtaatatttggcagaa SEQ ID NO: 1379 TRAJ7*01 tgtaatacacttacacagtgtgactatgggaacaacagactcgcttttgggaagggg aaccaagtggtggtcataccaagtaagtgagctgggatcctcc SEQ ID NO: 1380 TRAJ8*01 tacagagttatgtcagagtgtgaacacaggctttcagaaacttgtatttggaactgg cacccgacttctggtcagtccaagtaagtcaaatctgcagaaa SEQ ID NO: 1381 TRAJ9*01 cgcagtgcaaatcactgtgggaaatactggaggcttcaaaactatctttggagcagg aacaagactatttgttaaagcaagtaagttccatgaaataacc SEQ ID NO: 1382 TRBJ1-1*01 ttttcaccttgacccctgtcactgtgtgaacactgaagctttctttggacaaggcac cagactcacagttgtaggtaagacatttttcaggttcttttgc SEQ ID NO: 1383 TRBJ1-2*01 ttttagagtggctatattcttatgtgctaactatggctacaccttcggttcggggac caggttaaccgttgtaggtaaggctgggggtctctaggagggg SEQ ID NO: 1384 TRBJ1-3*01 tttgaagtggccctgggaggctgtgctctggaaacaccatatattttggagagggaa gttggctcactgttgtaggtgagtaagtcaaggctggacagct SEQ ID NO: 1385 TRBJ1-4*01 ttccttccagtctttaatgttgtgcaactaatgaaaaactgttttttggcagtggaa cccagctctctgtcttgggtatgtaaaagacttctttcgggat SEQ ID NO: 1386 TRBJ1-5*01 tttgccacactcatgatgcactgtgtagcaatcagccccagcattttggtgatggga ctcgactctccatcctaggtaagttggcagaatcagggtggta SEQ ID NO: 1387 TRBJ1-6*01 ttatctaagcctctgcagctgtgctcctataattcacccctccactttgggaatggg accaggctcactgtgacaggtatgggggctccactcttgactc SEQ ID NO: 1388 TRBJ1-6*02 ttatctaagcctctgcagctgtgctcctataattcacccctccactttgggaacggg accaggctcactgtgacaggtatgggggctccactcttgactc SEQ ID NO: 1389 TRBJ2-1*01 ttctgggcagccccttcccactgtgctcctacaatgagcagttcttcgggccaggga cacggctcaccgtgctaggtaagaagggggctccaggtgggag SEQ ID NO: 1390 TRBJ2-2*01 tgcgccagggtccccagggctgtgcgaacaccggggagctgttttttggagaaggct ctaggctgaccgtactgggtaaggaggcggctggggctccgga SEQ ID NO: 1391 TRBJ2-2P*01 agctgccccactctgagaggggctgtgctgagaggcgctgctgggcgtctgggcgga ggactcctggttctgggtgctgggagagcgatggggctctcag SEQ ID NO: 1392 TRBJ2-3*01 ttttgtcctgggcctccaggctgtgagcacagatacgcagtattttggcccaggcac ccggctgacagtgctcggtaagcgggggctcccgctgaagccc SEQ ID NO: 1393 TRBJ2-4*01 ttctgtgccgcgtctcggggctgtgagccaaaaacattcagtacttcggcgccggga cccggctctcagtgctgggtaagctggggccgccgggggaccg SEQ ID NO: 1394 TRBJ2-5*01 tttttgtgcggggctcgggggccgtgaccaagagacccagtacttcgggccaggcac gcggctcctggtgctcggtgagcgcgggctgctggggcgcggg SEQ ID NO: 1395 TRBJ2-6*01 ttgcggggagtccccgggctgtgctctggggccaacgtcctgactttcggggccggc agcaggctgaccgtgctgggtgagttttcgcgggaccacccgg SEQ ID NO: 1396 TRBJ2-7*01 tttgcatgcgggggtgcacctccgtgctcctacgagcagtacttcgggccgggcacc aggctcacggtcacaggtgagattcgggcgtctccccaccttc SEQ ID NO: 1397 TRBJ2-7*02 tttgcatgcggggatgcacctccgtgctcctacgagcagtacgtcgggccgggcacc aggctcacggtcacaggtgagattcgggcgtctccccaccttc SEQ ID NO: 1398 TRDJ1*01 ttttggaacgtcctcaagtgctgtgacaccgataaactcatctttggaaaaggaacc cgtgtgactgtggaaccaagtaagtaactcattatttatctga SEQ ID NO: 1399 TRDJ2*01 tttttcgtaatgacgcctgtggtagtgctttgacagcacaactcttctttggaaagg gaacacaactcatcgtggaaccaggtaagttatgcattttact SEQ ID NO: 1400 TRDJ3*01 tgaggcactgtcataatgtgctcctgggacacccgacagatgtttttcggaactggc atcaaactcttcgtggagccccgtgagttgatctttttcctat SEQ ID NO: 1401 TRDJ4*01 atgagacatacaaaaaggtaatgccgccccagacccctgatctttggcaaaggaacc tatctggaggtacaacaac SEQ ID NO: 1402 TRGJ1*01 ttttgatatggactgaatcactgtggaattattataagaaactctttggcagtggaa caacactggttgtcacaggtaagtatcggaagaatacaacatt SEQ ID NO: 1403 TRGJ1*02 tactgtgccttgtgggaggtgcttattataagaaactctttggcagtggaacaacac ttgttgtcacaggt SEQ ID NO: 1404 TRGJ2*01 ttttgatatggactgaatcactgtggaattattataagaaactctttggcagtggaa caacacttgttgtcacaggtaagtatcggaagaatacaacatt SEQ ID NO: 1405 TRGJP*01 ataaaggcttctcaggtggtgggcaagagttgggcaaaaaaatcaaggtatttggtc ccggaacaaagcttatcattacaggtaagttttctttaaattt SEQ ID NO: 1406 TRGJP1*01 gatttttctagaagcttagaccggtgtgataccactggttggttcaagatatttgct gaagggactaagctcatagtaacttcacctggtaagt SEQ ID NO: 1407 TRGJP2*01 gatttttgtagaagcttagaccagtgtgatagtagtgattggatcaagacgtttgca aaagggactaggctcatagtaacttcgcctggtaagt

TABLE 2.3 Dilution Series Design Desired cell Equivalent fraction of polyclonal Theoretical final Total desired Jurkat- Number of Required (A037) DNA dilution DNA number of cells configuration desired Jurkat polyclonal Equivalent Jurkat DNA required Water concentration Dilution in 50 μL lymphocytes cells cells required (μL)^(‡) (μL) (μL) (ng/μL) 1 2.00E+05 1 2.00E+05 0 13.21 0.00 36.79 2.80 2 2.00E+05 0.1 2.00E+04 1.80E+05 13.21 of 1 in 10 dilution of 2.79 34.00 2.80 Dilution 1 3 2.00E+05 0.01 2.00E+03 1.98E+05 13.21 of 1 in 10 dilution of 3.07 33.72 2.80 Dilution 2 4 2.00E+05 0.001 2.00E+02 2.00E+05 13.21 of 1 in 10 dilution of 3.09 33.70 2.80 Dilution 3 5 2.00E+05 0.0001 2.00E+01 2.00E+05 13.21 of 1 in 10 dilution of 3.10 33.69 2.80 Dilution 4 6 2.00E+05 0.00001 2.00E+00 2.00E+05 13.21 of 1 in 10 dilution of 3.10 33.69 2.80 Dilution 5 ^(‡)Assumptions of note: Stock Jurkat Cell Line DNA Concentration: 10.6 ng/μL; Presumed lymphocyte DNA content: 0.0007 ng/cell

TABLE 2.4 Clinical, Pathology & Outcome Data Parameters Clinical Data Treatment Data Outcome Data Parameters Pathology Data Parameters Parameters Parameters Age at Diagnosis Morphology (small cell, large cell, First-line therapy Birthdate anaplastic) Gender Background (mixed or uniform Transplant (Yes/No) Diagnosis Date inflammatory infiltrates) Primary Site of Bone Marrow Status at Diagnosis Second-line or Date of Last Follow- Involvement (% of involvement by tumor, if subsequent additional up applicable) therapies Performance Primary Specimen Disposition Status Immunohistochemistry (0 = Alive; (positive/negative) 1 = Deceased) B symptoms CD2 International CD3 Prognostic Index Stage CD4 CBC at diagnosis CD5 Hb CD7 MCV CD8 Pit CD10 Neut CD21 Mono CD23 Eo CD30 Lymph CD56 Other CD57 Chemistry BCL6 LDH Ki67 Uric Acid EBER Albumin ALK Alk Phos PD1 ALT CXCL-13 AST Primary Specimen Flow Cytometry (positive/negative) BUN CD45 Calcium CD2 Chloride CD3 CO2 CD5 Creatinine CD4 Glucose CD7 Potassium CD8 Sodium CD10 Total Bilirubin CD19 Total protein CD20 CD30 TCR alpha/beta TCR gamma/delta Molecular Clonality (clonal/polyclonal) Other Cytogenetics(normal/abnormal) Classical FISH Serology (positive/negative) HIV HTLV-1

TABLE 2.5 Sample descriptions and flow cytometry data of the 6 actual patient lymphocyte specimens used for analytical validation Flow-cytometry Number of Cells Features (if Input for DNA “Clonal/Oligoclonal” vs Sample Name Description available) Isolation “Polyclonal” A037 Healthy Donor N/A 10,000,000 Polyclonal Patient Peripheral Blood Mononuclear Cells OV7 Mixed Ovarian 90% CD3+ 10,000,000 Polyclonal Tumour- 10% CD4+ Infiltrating 70% CD8+ Lymphocytes expanded with IL- 2 treatment EZM Cell suspension of N/A 10,000,000 Uncertain melanoma tumour (possible admixed with brisk CD3 tumour cells) infiltration TIL2 Melanoma 97% CD8+ 10,000,000 Oligoclonal tumour-infiltrating lymphocytes expanded in IL-2 STIM1 MART1-specific 99% CD8+ 10,000,000 Clonal/Oligoclonal cell line made from peptide stimulation of healthy donor PBMCs, FACS sorting and expansion of tetramer + cells L2D8 gp100-specific ~100% CD8+    10,000,000 Clonal/Oligoclonal tumour-infiltrating lymphocyte clone

TABLE 2.6 Cell lines used for analytical validation Reference Previously Documented/Known Cell Line Collection # TRGR Configurations CEM ATCC CCL-119 TRBV3-1*01-TRBD1*01-TRBJ2-3*01 (CCRF- TRBJ1-5-TRBJ2-1 (partial rearrangement) CEM) TRBV9-TRBD2 (partial rearrangement) TRGV3-TRGJ1/TRGJ2 TRGV4-TRGJ1/TRGJ2 JurKat DSMZ ACC-282 TRAV8-4-TRAJ3 TRBV12-3-TRBJ1-2 (partial rearrangement) MOLT4 ATCC CRL- TREV20-1*01-TRBD2*01-TRBJ2-1*01 1582 TRBV10-3-TRBD1*01-TR8J2-5 TRGV2-TRGJP1 TRGV2-TRGJP2 SUPT1 ATCC CRL- TRBV9*01-TRBD2*01-TRBJ2-1*01 1942 TRGV3-TRGJ1/TRGJ2 TRGV4-TRGJ1/TRGJ2

TABLE 1.1 Capture Sample Method Data Sample Sample Protocol Type Library input (ng) A037 healthy reference Sample_A037_PBMC_TCR_A_all A037_PBMC CapSeq_One-Step_V 100 Sample_A037_PBMC_TCR_B_all A037_PBMC CapSeq_One-Step_V 200 Sample_A037_PBMC_TCR_D_all A037_PBMC CapSeq_One-Step_V 600 Sample_A037_PBMC_TCR_E_all A037_PBMC CapSeq_One-Step_V 800 Sample_A037_PBMC_TCR_F_all A037_PBMC CapSeq_One-Step_V 1000 Sample_A037_PBMC_TCR_G_all A037_PBMC CapSeq_One-Step_V 200 Sample_A037_PBMC_TCR_H_all A037_PBMC CapSeq_One-Step_V 600 Sample_A037_PBMC_TCR_J_all A037_PBMC CapSeq_One-Step_V 200 Sample_A037_PBMC_TCR_K_all A037_PBMC CapSeq_One-Step_V 600 Sample_A037_PBMC_TCR_L_all A037_PBMC CapSeq_One-Step_V 1000 Sample_16_01_A037_PBMC_TCR_F_all A037_PBMC CapSeq_One-Step_V 500 Sample_16_01_A037_PBMC_TCR_H_all A037_PBMC CapSeq_One-Step_V 250 Sample_A037_S1_all A037_PBMC CapSeq_One-Step_VJ 100 Sample_A037_PBMC_1S_all A037_PBMC CapSeq_One-Step_VJ 100 Sample_16_11_A037_PBMC_TCR_VJ_all A037_PBMC CapSeq_One-Step_VJ 100 Sample_A037_CD3_1S_all A037_CD3 CapSeq_One-Step_VJ 100 Cell lines and flow sorted M36_EZM flow_sorted CapSeq_One-Step_VJ 100 M36_TIL2 flow_sorted CapSeq_One-Step_VJ 100 OV7-TIL2 flow_sorted CapSeq_One-Step_VJ 100 SE14-2005 cell_line CapSeq_One-Step_VJ 100 SE14-2033 cell_line CapSeq_One-Step_VJ 100 SE14-2034 cell_line CapSeq_One-Step_VJ 100 SE14-2035 cell_line CapSeq_One-Step_VJ 100 STIM1 flow_sorted CapSeq_One-Step_VJ 100 L2D8 flow_sorted CapSeq_One-Step_VJ 100 Patient samples M14-10124 patient_tumor CapSeq_One-Step_VJ 100 M14-11153 patient_tumor CapSeq_One-Step_VJ 100 M14-11567 patient_tumor CapSeq_One-Step_VJ 100 M14-11587 patient_tumor CapSeq_One-Step_VJ 100 M14-11721 patient_tumor CapSeq_One-Step_VJ 100 M14-11770 patient_tumor CapSeq_One-Step_VJ 100 M14-12217 patient_tumor CapSeq_One-Step_VJ 100 M14-12649 patient_tumor CapSeq_One-Step_VJ 100 M14-12728 patient_tumor CapSeq_One-Step_VJ 100 M14-12753 patient_tumor CapSeq_One-Step_VJ 100 M14-13167 patient_tumor CapSeq_One-Step_VJ 100 M14-13300 patient_tumor CapSeq_One-Step_VJ 100 M14-13750 patient_tumor CapSeq_One-Step_VJ 100 M14-14570 patient_tumor CapSeq_One-Step_VJ 100 M14-14625 patient_tumor CapSeq_One-Step_VJ 100 M14-14907 patient_tumor CapSeq_One-Step_VJ 100 M14-14951 patient_tumor CapSeq_One-Step_VJ 100 M14-14962 patient_tumor CapSeq_One-Step_VJ 100 M14-1508 patient_tumor CapSeq_One-Step_VJ 100 M14-15119 patient_tumor CapSeq_One-Step_VJ 100 M14-3271 patient_tumor CapSeq_One-Step_VJ 100 M14-4454 patient_tumor CapSeq_One-Step_VJ 100 M14-5819 patient_tumor CapSeq_One-Step_VJ 100 M14-5875 patient_tumor CapSeq_One-Step_VJ 100 M14-6143 patient_tumor CapSeq_One-Step_VJ 100 M14-6430 patient_tumor CapSeq_One-Step_VJ 100 M14-6443 patient_tumor CapSeq_One-Step_VJ 100 M14-6502 patient_tumor CapSeq_One-Step_VJ 100 M14-6885 patient_tumor CapSeq_One-Step_VJ 100 M14-7046 patient_tumor CapSeq_One-Step_VJ 100 M14-7049 patient_tumor CapSeq_One-Step_VJ 100 M14-7053 patient_tumor CapSeq_One-Step_VJ 100 M14-7107 patient_tumor CapSeq_One-Step_VJ 100 M14-7554 patient_tumor CapSeq_One-Step_VJ 100 M14-7568 patient_tumor CapSeq_One-Step_VJ 100 M14-7691 patient_tumor CapSeq_One-Step_VJ 100 M14-7700 patient_tumor CapSeq_One-Step_VJ 100 M14-7782 patient_tumor CapSeq_One-Step_VJ 100 M14-7862 patient_tumor CapSeq_One-Step_VJ 100 M14-7884 patient_tumor CapSeq_One-Step_VJ 100 M14-7992 patient_tumor CapSeq_One-Step_VJ 100 M14-8132 patient_tumor CapSeq_One-Step_VJ 100 M14-8272 patient_tumor CapSeq_One-Step_VJ 100 M14-8639 patient_tumor CapSeq_One-Step_VJ 100 M14-8668 patient_tumor CapSeq_One-Step_VJ 100 M14-8740 patient_tumor CapSeq_One-Step_VJ 100 M14-8913 patient_tumor CapSeq_One-Step_VJ 100 M14-8914 patient_tumor CapSeq_One-Step_VJ 100 M14-9212 patient_tumor CapSeq_One-Step_VJ 100 M14-9801 patient_tumor CapSeq_One-Step_VJ 100 M15-1195 patient_tumor CapSeq_One-Step_VJ 100 M15-1330 patient_tumor CapSeq_One-Step_VJ 100 M15-1470 patient_tumor CapSeq_One-Step_VJ 100 M15-1556 patient_tumor CapSeq_One-Step_VJ 100 M15-1825 patient_tumor CapSeq_One-Step_VJ 100 M15-1867 patient_tumor CapSeq_One-Step_VJ 100 M15-1883 patient_tumor CapSeq_One-Step_VJ 100 M15-237 patient_tumor CapSeq_One-Step_VJ 100 M15-2603 patient_tumor CapSeq_One-Step_VJ 100 M15-2779 patient_tumor CapSeq_One-Step_VJ 100 M15-3091 patient_tumor CapSeq_One-Step_VJ 100 M15-587 patient_tumor CapSeq_One-Step_VJ 100 M15-795 patient_tumor CapSeq_One-Step_VJ 100 M15-933 patient_tumor CapSeq_One-Step_VJ 100

TABLE 1.2 Capture Sample Read Counts Sample total reads on-target reads off-target reads on-target ratio merged reads reads after threshold A037 healthy reference Sample_A037_PBMC_TCR_A_all 1961529 96884 1864620 0.049392081 1961504 1900159 Sample_A037_PBMC_TCR_B_all 9915634 865444 9050165 0.087280753 9915609 9488814 Sample_A037_PBMC_TCR_D_all 11554469 359807 11194637 0.031140072 11554444 10839947 Sample_A037_PBMC_TCR_E_all 8208382 4019972 4188385 0.489739878 8208357 8069762 Sample_A037_PBMC_TCR_F_all 13434420 3925996 9508399 0.292234127 13434395 13076224 Sample_A037_PBMC_TCR_G_all 11585206 217323 11367858 0.018758665 11585181 11162632 Sample_A037_PBMC_TCR_H_all 8680363 1631345 7048993 0.187935113 8680338 8302862 Sample_A037_PBMC_TCR_J_all 17147171 504177 16642969 0.029402926 17147146 14908072 Sample_A037_PBMC_TCR_K_all 8812446 518449 8293972 0.058831453 8812421 7851064 Sample_A037_PBMC_TCR_L_all 21053845 429885 20623935 0.020418361 21053820 17568322 Sample_16_01_A037_PBMC_TCR_F_all 4457394 958772 3498597 0.215096983 4457369 4389100 Sample_16_01_A037_PBMC_TCR_H_all 6835579 1719308 5116246 0.25152339 6835554 6750376 Sample_A037_S1_all 1920124 1082540 837559 0.563786505 1920099 1867339 Sample_A037_PBMC_1S_all 4868959 2120537 2748397 0.435521638 4768430 4706036 Sample_16_11_A037_PBMC_TCR_VJ_all 1433221 413057 1020139 0.288201889 1433196 1427599 Sample_A037_CD3_1S_all 4701054 2361517 2339512 0.502337774 4701029 4651006 Cell lines and flow sorted M36_EZM 2318060 1380043 937992 0.595343951 2318035 2255858 M36_TIL2 1569122 769525 799572 0.490417571 1569097 1518502 OV7-TIL2 2392656 1271622 1121009 0.531468795 2392631 2320790 SE14-2005 1291244 476090 815129 0.368706457 1291219 1216685 SE14-2033 1339529 662257 677247 0.494395418 1339504 1293618 SE14-2034 1278441 564484 713932 0.441540908 1278416 1240462 SE14-2035 1678562 743158 935379 0.442734912 1678537 1611636 STIM1 1880814 900492 980297 0.478777806 1880789 1827853 L2D8 1651306 910355 740926 0.551293946 1651281 1603088 Patient samples M14-10124 3874239 1363917 2510297 0.352047718 3874214 3641564 M14-11153 4921789 1618479 3303285 0.328839574 4921764 4871138 M14-11567 4961317 1742809 3218483 0.351279509 4961292 4808248 M14-11587 4284116 1363269 2920822 0.318214773 4284091 4230674 M14-11721 5480831 1885151 3595655 0.343953499 5480806 5423859 M14-11770 5405827 415885 4989917 0.076932725 5405802 5177500 M14-12217 5135793 1690789 3444979 0.329216734 5135768 5098364 M14-12649 7798007 2759564 5038418 0.353880677 7797982 7715502 M14-12728 5006452 739003 4267424 0.147610124 5006427 4799839 M14-12753 5044768 1512141 3532602 0.299744408 5044743 4998359 M14-13167 2912824 980216 1932583 0.336517414 2912799 2891403 M14-13300 6403753 976423 5427305 0.15247668 6403728 6226299 M14-13750 6648103 894302 5753776 0.134519877 6648078 6520478 M14-14570 4577658 964191 3613442 0.210629759 4577633 4516409 M14-14625 4919394 671943 4247426 0.136590604 4919369 4678232 M14-14907 6045676 1996999 4048652 0.330318562 6045651 5967138 M14-14951 4339950 334232 4005693 0.077012869 4339925 4253000 M14-14962 2621464 397567 2223872 0.151658386 5799400 5552790 M14-1508 6616839 3224927 3391887 0.487381815 6616814 6538041 M14-15119 4825285 658203 4167057 0.136407072 4825260 4721235 M14-3271 7352598 3438740 3913833 0.467690468 7352573 7230944 M14-4454 7015117 3588858 3426234 0.511589187 7015092 6912948 M14-5819 6427168 2297299 4129844 0.357435654 6427143 6377748 M14-5875 6466998 2244807 4222166 0.347117318 6466973 6357148 M14-6143 5149354 740986 4408343 0.143898827 5149329 4979117 M14-6430 7717729 4019388 3698316 0.520799318 7717704 7610950 M14-6443 5310114 1719071 3591018 0.323735234 5310089 5258149 M14-6502 6854324 449983 6404316 0.065649508 6854299 6571528 M14-6885 4473140 636717 3836398 0.142342292 4473115 4255663 M14-7046 2901414 389561 2511828 0.134265913 2901389 2690711 M14-7049 4194422 328356 3866041 0.078283969 4194397 4104557 M14-7053 4534911 634273 3900613 0.139864487 4534886 4132215 M14-7107 3653179 489927 3163227 0.134109771 3653154 3443643 M14-7554 6905643 3346628 3558990 0.484622214 6905618 6814973 M14-7568 5989679 2953254 3036400 0.49305714 5989654 5933921 M14-7691 4715544 2109689 2605830 0.447390375 4715519 4633852 M14-7700 6664469 2293770 4370674 0.344178959 6664444 6605136 M14-7782 6155725 3173681 2982019 0.515565754 6155700 6034814 M14-7862 5025139 361053 4664061 0.071849356 5025114 4886216 M14-7884 5190944 361315 4829604 0.069604873 5190919 5085124 M14-7992 5745439 2814128 2931286 0.489802085 5745414 5649598 M14-8132 5328896 1787753 3541118 0.335482809 5328871 5288026 M14-8272 6030251 3161144 2869082 0.524214332 6030226 5874655 M14-8639 7376555 3887519 3489011 0.527010102 7376530 7249500 M14-8668 5401734 2916998 2484711 0.540011411 5401709 5338260 M14-8740 5346366 233692 5112649 0.043710438 5346341 5202430 M14-8913 6495674 3372030 3123619 0.51911934 6495649 6455304 M14-8914 6562054 3324004 3238025 0.506549321 6562029 6458959 M14-9212 4503869 1426322 3077522 0.316688163 4503844 4452847 M14-9801 5502711 387341 5115345 0.07039094 5502686 5398233 M15-1195 6305701 392089 5913587 0.062180081 6305676 6065963 M15-1330 8302037 2704496 5597516 0.325762942 8302012 8107829 M15-1470 3834967 292000 3542942 0.076141464 3834942 3767575 M15-1556 6935912 3615566 3320321 0.521281989 6935887 6892616 M15-1825 6078396 1963007 4115364 0.322948192 6078371 6014071 M15-1867 6865892 3557974 3307893 0.518210016 6865867 6816073 M15-1883 6227227 3087220 3139982 0.495761597 6227202 6169114 M15-237 6215041 2213245 4001771 0.356111086 6215016 6155386 M15-2603 5639514 2766020 2873469 0.490471342 5639489 5564062 M15-2779 5680891 2792325 2888541 0.49152941 5680866 5628837 M15-3091 6906018 3575635 3330358 0.517756397 6905993 6843330 M15-587 3920359 589850 3330484 0.15045816 3920334 3808959 M15-795 4275264 769512 3505727 0.179991692 4275239 4205077 M15-933 6551470 3277319 3274126 0.500241778 6551445 6481344

TABLE 1.3 Capture Sample V and J Calls alpha beta gamma delta unmatched single absent Sample VJ calls VJ calls VJ calls VJ calls VJ calls V or J V and J A037 healthy reference Sample_A037_PBMC_TCR_A_all 30 111 46 0 0 171866 1728107 Sample_A037_PBMC_TCR_B_all 473 806 538 0 0 1634949 7852049 Sample_A037_PBMC_TCR_D_all 298 244 127 1 0 583395 10255883 Sample_A037_PBMC_TCR_E_all 4470 1956 2916 82 5 5486404 2573930 Sample_A037_PBMC_TCR_F_all 3932 1815 3169 84 6 5949549 7117670 Sample_A037_PBMC_TCR_G_all 101 186 78 15 0 420033 10742220 Sample_A037_PBMC_TCR_H_all 1607 1125 252 12 4 2160797 6139066 Sample_A037_PBMC_TCR_J_all 323 139 135 4 2 1112523 13794947 Sample_A037_PBMC_TCR_K_all 352 169 200 6 0 1027278 6823060 Sample_A037_PBMC_TCR_L_all 259 111 136 8 3 1057487 16510319 Sample_16_01_A037_PBMC_TCR_F_all 925 363 628 25 1 3437777 949382 Sample_16_01_A037_PBMC_TCR_H_all 1397 763 1015 21 2 4575171 2172015 Sample_A037_S1_all 1052 606 734 12 2 1255308 609626 Sample_A037_PBMC_1S_all 1008 599 834 26 1 2536312 2167257 Sample_16_11_A037_PBMC_TCR_VJ_all 340 161 329 11 0 934369 492390 Sample_A037_CD3_1S_all 6368 3264 4805 123 7 2753833 1882607 Cell lines and flow sorted M36_EZM 138 94 94 0 0 1521931 733602 M36_TIL2 2136 1579 1963 4 7 1015956 496858 OV7-TIL2 2619 1879 1918 52 1 1515855 798467 SE14-2005 2450 1293 2070 0 0 818261 392612 SE14-2033 1389 924 1344 0 0 895089 394873 SE14-2034 1910 2833 1377 0 0 856362 377981 SE14-2035 3031 2017 2157 0 0 1020846 583586 STIM1 3068 1524 2503 0 0 1192227 628532 L2D8 2074 962 948 0 0 1060361 538744 Patient samples M14-10124 1971 1098 1674 48 0 2380500 1256274 M14-11153 585 283 628 9 0 2811142 2058492 M14-11567 1423 901 1278 8 6 2599812 2204821 M14-11587 182 251 142 0 2 2473198 1756900 M14-11721 210 65 192 0 3 3272558 2150832 M14-11770 17 36 25 0 0 768985 4408438 M14-12217 343 141 2481 648 0 2982597 2112155 M14-12649 1267 857 1327 4 3 4868928 2843117 M14-12728 986 607 967 14 0 1069367 3727899 M14-12753 1600 960 2053 40 1 2485050 2508656 M14-13167 215 87 248 22 0 1710714 1180118 M14-13300 1620 688 2344 13 1 1571492 4650142 M14-13750 1995 1039 2144 108 7 1527402 4987784 M14-14570 155 163 290 45 0 1742539 2773218 M14-14625 1083 562 967 7 1 1084783 3590830 M14-14907 981 247 494 15 0 3030809 2934593 M14-14951 166 84 174 4 3 613083 3639487 M14-14962 623 332 545 7 0 1160605 4390679 M14-1508 3489 2654 3136 19 1 4047376 2481367 M14-15119 4218 1546 1551 0 3 986010 3727908 M14-3271 4607 2563 3523 64 6 4297650 2922532 M14-4454 1974 904 1199 11 6 4479570 2429285 M14-5819 186 86 271 2 1 2435125 3942078 M14-5875 484 371 533 12 0 3411599 2944150 M14-6143 575 241 481 1 0 1235788 3742032 M14-6430 863 471 705 39 0 4942133 2666740 M14-6443 0 0 0 0 0 2721814 2536336 M14-6502 119 77 140 0 0 913846 5657347 M14-6885 1274 727 888 4 3 985106 3267662 M14-7046 497 190 442 5 4 615177 207439 M14-7049 5 2 396 611 0 630487 3473057 M14-7053 409 228 420 23 0 936724 3194412 M14-7107 1122 577 915 2 1 797093 2643934 M14-7554 901 469 861 24 1 1741112 5071606 M14-7568 2181 861 1674 141 2 3472975 2456088 M14-7691 5077 4087 4193 0 0 2889813 1730683 M14-7700 536 342 860 6 0 4144765 2458628 M14-7782 682 417 723 21 0 3850370 2182602 M14-7862 264 104 232 0 2 735636 4149979 M14-7884 340 228 434 0 0 739308 4344815 M14-7992 1987 1338 1755 12 0 3223885 2420622 M14-8132 229 150 287 3 0 3138235 2149123 M14-8272 273 223 299 0 0 3574689 2299172 M14-8639 638 335 605 29 0 4327667 2920227 M14-8668 140 107 117 0 2 3224632 2113263 M14-8740 741 374 842 0 0 643355 4557119 M14-8913 451 268 447 12 0 3838965 2615162 M14-8914 868 350 718 1 1 4020234 2436788 M14-9212 1208 712 1318 7 0 2691103 1758500 M14-9801 407 183 387 2 0 779518 4617737 M15-1195 119 84 83 0 0 767911 5297767 M15-1330 8600 3192 5559 101 7 5264470 2825901 M15-1470 327 203 562 0 1 561308 3205175 M15-1556 446 253 483 6 2 3805780 3085647 M15-1825 969 508 1009 13 0 3034468 2977105 M15-1867 269 127 286 34 0 2887666 3927692 M15-1883 2011 885 1324 82 4 3843001 2321808 M15-237 276 191 275 0 1 3558414 2596230 M15-2603 1559 821 1398 24 0 3448607 2111654 M15-2779 1475 761 1463 41 3 3503916 2121179 M15-3091 200 84 143 9 0 3519287 3323608 M15-587 647 375 627 11 2 931289 2876009 M15-795 360 159 355 7 3 1064180 3140014 M15-933 1187 596 1118 13 3 2942292 3536136

TABLE 1.4 Capture Sample Unique V and J Calls alpha unique VJ beta unique gamma unique delta unique VJ total Unique VJ Sample counts VJ counts VJ counts counts unique VJ normalized to input A037 healthy reference Sample_A037_PBMC_TCR_A_all 11 20 6 0 37 0.37 Sample_A037_PBMC_TCR_B_all 44 65 18 0 127 0.64 Sample_A037_PBMC_TCR_D_all 213 158 25 1 397 0.66 Sample_A037_PBMC_TCR_E_all 955 405 49 3 1412 1.77 Sample_A037_PBMC_TCR_F_all 1343 527 49 6 1925 1.93 Sample_A037_PBMC_TCR_G_all 8 18 5 1 32 0.16 Sample_A037_PBMC_TCR_H_all 502 305 24 2 833 1.39 Sample_A037_PBMC_TCR_J_all 192 90 21 3 306 1.53 Sample_A037_PBMC_TCR_K_all 268 122 32 4 426 0.71 Sample_A037_PBMC_TCR_L_all 220 85 24 3 332 0.33 Sample_16_01_A037_PBMC_TCR_F_all 414 175 41 2 632 1.26 Sample_16_01_A037_PBMC_TCR_H_all 463 235 34 3 735 2.94 Sample_A037_S1_all 446 227 36 3 712 7.12 Sample_A037_PBMC_15_all 466 253 36 4 759 7.59 Sample_16_11_A037_PBMC_TCR_VJ_all 263 125 36 3 427 4.27 Sample_A037_CD3_15_all 1704 710 54 7 2475 24.75 Cell lines and flow sorted M36_EZM 67 41 15 0 123 1.23 M36_TIL2 244 163 38 1 446 4.46 OV7-TIL2 143 114 49 5 311 3.11 SE14-2005 6 13 5 0 24 0.24 SE14-2033 14 3 5 0 22 0.22 SE14-2034 5 16 7 0 28 0.28 SE14-2035 9 9 6 0 24 0.24 STIM1 101 71 23 0 195 1.95 L2D8 6 3 3 0 12 0.12 Patient samples M14-10124 225 142 33 2 402 4.02 M14-11153 137 63 28 2 230 2.30 M14-11567 242 147 39 1 429 4.29 M14-11587 37 39 15 0 91 0.91 M14-11721 35 14 21 0 70 0.70 M14-11770 14 16 8 0 38 0.38 M14-17217 59 32 15 1 107 1.07 M14-12649 174 132 34 1 341 3.41 M14-12728 433 229 47 4 713 7.13 M14-12753 178 104 25 4 311 3.11 M14-13167 44 19 21 2 86 0.86 M14-13300 221 146 33 2 402 4.02 M14-13750 410 201 46 5 662 6.62 M14-14570 34 33 18 3 88 0.88 M14-14625 485 242 50 2 779 7.79 M14-14907 227 62 26 2 317 3.17 M14-14951 73 43 24 1 141 1.41 M14-14962 327 173 41 3 544 5.44 M14-1508 352 203 46 5 606 6.06 M14-15119 19 18 7 0 44 0.44 M14-3271 798 405 53 4 1260 12.60 M14-4454 260 132 31 2 425 4.25 M14-5819 53 23 24 1 101 1.01 M14-5875 99 79 32 1 211 2.11 M14-6143 278 113 40 1 432 4.32 M14-6430 173 112 29 3 317 3.17 M14-6443 0 0 0 0 0 0.00 M14-6502 66 37 27 0 130 1.30 M14-6885 513 262 32 3 810 8.10 M14-7046 157 70 23 1 251 2.51 M14-7049 3 1 3 3 10 0.10 M14-7053 148 89 35 4 276 2.76 M14-7107 456 205 45 1 707 7.07 M14-7554 164 103 29 5 301 3.01 M14-7568 480 186 39 5 710 7.10 M14-7691 237 146 43 0 426 4.26 M14-7700 105 64 26 1 196 1.96 M14-7782 150 99 34 2 285 2.85 M14-7862 76 32 22 0 130 1.30 M14-7884 171 106 39 0 316 3.16 M14-7992 258 160 34 2 454 4.54 M14-8132 34 28 21 1 84 0.84 M14-8272 72 60 29 0 161 1.61 M14-8639 125 77 27 3 232 2.32 M14-6668 44 32 19 0 95 0.95 M14-8740 17 9 13 0 39 0.39 M14-8913 90 61 30 2 183 1.83 M14-8914 177 75 29 1 282 2.82 M14-9212 190 128 27 3 348 3.48 M14-9801 85 41 29 1 156 1.56 M15-1195 45 32 24 0 101 1.01 M15-1330 1019 362 55 6 1442 14.42 M15-1470 50 38 28 0 116 1.16 M15-1556 120 59 24 1 204 2.04 M15-1825 214 121 30 1 366 3.66 M15-1867 90 46 32 2 170 1.70 M15-1883 435 194 33 6 668 6.68 M15-237 51 36 21 0 108 1.08 M15-2603 294 169 57 3 523 5.23 M15-2779 349 185 31 5 570 5.70 M15-3091 44 25 15 1 85 0.85 M15-587 309 159 39 4 511 5.11 M15-795 174 73 38 2 287 2.87 M15-933 353 170 57 1 581 5.81

TABLE 1.5 Capture Sample Unique CDR3 Calls Unique CDR3 alpha total beta total gamma total delta total total unique normalized Sample unique CDR3 unique CDR3 unique CDR3 unique CDR3 CDR3 to input A037 healthy reference Sample_A037_PBMC_TCR_A_all 12 27 9 0 48 0.48 Sample_A037_PBMC_TCR_B_all 63 104 31 0 198 0.99 Sample_A037_PBMC_TCR_D_all 229 188 65 2 484 0.81 Sample_A037_PBMC_TCR_E_all 1367 778 348 21 2514 3.14 Sample_A037_PBMC_TCR_F_all 2066 1100 540 24 3730 3.73 Sample_A037_PBMC_TCR_G_all 11 23 11 3 48 0.24 Sample_A037_PBMC_TCR_H_all 633 482 62 3 1180 1.97 Sample_A037_PBMC_TCR_J_all 216 104 48 4 372 1.86 Sample_A037_PBMC_TCR_K_all 297 148 82 5 532 0.89 Sample_A037_PBMC_TCR_L_all 242 99 63 8 412 0.41 Sample_16_01_A037_PBMC_TCR_F_all 482 229 155 14 880 1.76 Sample_16_01_A037_PBMC_TCR_H_all 555 330 158 4 1047 4.19 Sample_A037_S1_all 509 303 141 5 958 9.58 Sample_A037_PBMC_15_all 539 344 157 13 1053 10.53 Sample_16_11_A037_PBMC_TCR_VJ_all 293 142 114 8 557 5.57 Sample_A037_CD3 _15_all 2840 1672 691 47 5250 52.50 Cell lines and flow sorted M36_EZM 70 48 26 0 144 1.44 M36_TIL2 310 25 101 2 439 4.38 OV7-TIL2 219 192 83 9 503 5.03 SE14-2005 32 29 21 0 82 0.82 SE14-2033 32 21 10 0 63 0.63 SE14-2034 10 66 8 0 84 0.84 SE14-2035 33 39 23 0 95 0.95 STIM1 160 136 55 0 351 3.51 L2D8 14 21 10 0 45 0.45 Patient samples M14-10124 279 201 101 3 584 5.84 M14-11153 151 80 54 2 287 2.87 M14-11567 287 193 97 1 578 5.78 M14-11587 41 57 30 0 128 1.28 M14-11721 39 17 28 0 84 0.84 M14-11770 14 16 11 0 41 0.41 M14-12217 66 43 52 18 179 1.79 M14-12649 206 185 89 1 491 4.81 M14-12728 494 323 183 7 1007 10.07 M14-12753 223 164 79 10 476 4.76 M14-13167 55 23 32 6 116 1.16 M14-13300 253 216 102 6 577 5.77 M14-13750 516 313 167 20 1016 10.16 M14-14570 35 40 34 8 117 1.17 M14-14625 562 321 193 3 1079 10.79 M14-14907 255 75 66 3 399 3.99 M14-14951 76 47 42 2 167 1.67 M14-14962 371 224 140 5 740 7.40 M14-1508 448 314 163 8 933 9.33 M14-15119 83 67 10 0 160 1.60 M14-3271 1084 714 275 12 2085 20.85 M14-4454 303 170 84 4 561 5.61 M14-5819 57 31 40 1 129 1.29 M14-5875 114 101 68 3 286 2.86 M14-6143 308 140 108 1 557 5.57 M14-6430 202 139 71 5 417 4.17 M14-6443 0 0 0 0 0 0.00 M14-6502 69 38 50 0 157 1.57 M14-6885 613 381 164 3 1161 1.61 M14-7046 177 78 72 3 330 3.30 M14-7049 3 1 13 11 28 0.28 M14-7053 162 109 79 10 360 3.60 M14-7107 532 290 158 1 981 9.81 M14-7554 189 129 78 13 409 4.09 M14-7568 583 252 138 10 983 9.83 M14-7691 317 301 99 0 717 7.17 M14-7700 123 82 74 1 280 2.80 M14-7782 166 125 75 4 370 3.70 M14-7862 82 38 37 0 157 1.57 M14-7884 181 125 102 0 408 4.08 M14-7992 306 231 118 3 658 6.58 M14-8132 37 34 33 1 105 1.05 M14-8272 77 73 50 0 200 2.00 M14-8639 140 99 65 8 312 3.12 M14-8668 45 35 26 0 106 1.06 M14-8740 31 21 16 0 68 0.68 M14-8913 114 78 53 5 250 2.50 M14-8914 212 100 78 1 391 3.91 M14-9212 224 168 85 3 480 4.80 M14-9801 104 52 42 1 199 1.99 M15-1195 48 36 32 0 116 1.16 M15-1330 1469 619 279 15 2382 23.82 M15-1470 57 44 50 0 151 1.51 M15-1556 127 71 56 1 255 2.55 M15-1825 259 147 108 2 516 5.16 M15-1867 96 54 59 4 213 2.13 M15-1883 520 284 120 11 935 9.35 M15-237 58 45 32 0 135 1.35 M15-2603 351 220 123 4 698 6.98 M15-2779 408 247 123 7 785 7.85 M15-3091 47 29 25 2 103 1.03 M15-587 346 214 113 6 679 6.79 M15-795 188 85 87 3 363 3.63 M15-933 418 242 162 3 825 8.25

TABLE 2 Cell Line Identified VJ Rearrangements Cell Reference Line Internal Collection # Alpha Beta Gamma Delta Previously Documented/Known TCR Configurations CEM SE14- ATCC CCL-119 NA TRBV3-1*01-TRBD1*01-TRBJ2-3*01 TRGV3-TRGJ1/TRGJ2 NA 2035 TRBJ1-5-TRBJ2-1 (partial TRGV4-TRGJ1/TRGJ2 rearrangement) TRBV9-TRBD2 (partial rearrangement) Alpha (Counts) Beta (Counts) Gamma (Counts) Delta Observed TRAV27#1TRAJ40#1 (987) TRBV3-1#1TRBJ2-3#1 (1087) TRGV4#2TRGJ2#1 ND (809) TRAV29_DV5#1TRAJ4#1 TRBV3-2#3TRBJ2-3#1 (512) TRGV3#2TRGJ2#1 (765) (604) TRAV29_DV5#3TRAJ4#1 (45) TRBV3-2#3TRBJ2-4#1 (45) TRGV3#1TRGJ2#1 (228) TRAV27#3TRAJ40#1 (3) TRBV3-1#1TRBJ2-5#1 (8) TRGV5#1TRGJ2#1 (106) TRAV27#2TRAJ40#1 (1) TRBV3-1#1TRBJ2-4#1 (4) TRGV4#1TRGJ2#1 (1) TRAV8-6#2TRAJ20#1 (1) TRBV3-1#1TRBJ2-6#1 (2) TRBV3-2#3TRBJ2-6#1 (2) TRBV9#2TRBJ2-1#1 (1) Previously Documented/Known TCR Configurations Jurkat SE14- DSMZ ACC- TRAV8-4-TRAJ3 TRBV12-3-TRBJ1-2 (partial TRGV8-TRGJ1/TRGJ2 NA 2033 282 rearrangement) TRGV11-TRGJ1/TRGJ2 Observed TRAV8-4#6TRAJ3#1 (1000) TRBV12-4#1TRBJ1-2#1 (608) TRGV8#1TRGJ2#1 ND (545) TRAV8-4#2TRAJ3#1 (118) TRBV12-4#2TRBJ1-2#1 (137) TRGV11#1TRGJ1#1 (272) TRAV12-3#2TRAJ26#1 (16) TRBV12-3#1TRBJ1-2#1 (16) TRGV11#2TRGJ1#1 (202) TRAV17#1TRAJ24#2 (7) TRGV11#1TRGJ2#1 (12) TRAV17#1TRAJ16#1 (4) TRGV11#2TRGJ2#1 (1) TRAV17#1TRAJ29#1 (3) TRAV14_DV4#2TRAJ24#2 (2) TRAV16#1TRAJ29#1 (1) TRAV17#1TRAJ32#1 (1) TRAV29_DVS#1TRAJ4#1 (1) TRAV9-2#1TRAJ29#1 (1) Previously Documented/Known TCR Configurations MOLT4 SE14- ATCC CRL- NA TRBV20-1*01-TRBD2*01-TRBJ2- TRGV2-TRGJP1 NA 2034 1582 1*01 TRBV10-3-TRBD1*01-TRBJ2-5 TRGV2-TRGJP2 Observed TRAV1-1#1TRAJ33#1 (799) TRBV20-1#1TRBJ2-1#1 (937) TRGV2#1TRGJP2#1 ND (524) TRAV1-1#1TRAJ24#2 (621) TRBV10-3#2TRBJ2-5#1 (724) TRGV2#2TRGJP1#1 (496) TRAV1-1#2TRAJ24#2 (79) TRBV20_OR9-2#3TRBJ2-1#1 (384) TRGV8#1TRGJP1#1 (1) TRAV1-1#2TRAJ33#1 (1) TRBV10-3#2TRBJ2-6#1 (91) TRBV20-1#7TRBJ2-1#1 (3) TRBV20_OR9-2#3TRBJ2-2#1 (2) TRBV20-1#1TRBJ2-2#1 (1) TRBV20-1#3TRBJ2-1#1 (1) Previously Documented/Known TCR Configurations SUPT1 SE14- ATCC CRL- NA TRBV9*01-TRBD2*01-TRVJ2-1*01 TRGV3-TRGJ1/TRGJ2 NA 2005 1942 TRGV4-TRGJ1/TRGJ2 Observed TRAV1-1#1TRAJ12#1 (1110) TRBV9#2TRBJ2-1#1 (971) TRGV3#2TRGJ2#1 ND (683) TRAV1-1#2TRAJ8#1 (836) TRBV9#1TRBJ2-1#1 (137) TRGV4#1TRGJ2#1 (449) TRAV1-1#1TRAJ8#1 (263) TRBV9#2TRBJ2-2#1 (9) TRGV4#2TRGJ2#1 (367) TRAV1-1#2TRAJ12#1 (4) TRBV5-3#1TRBJ2-5#1 (8) TRGV3#1TRGJ2#1 (198) TRAV29_DV5#1TRAJ26#1 (3) TRBV5-3#2TRBJ2-5#1 (4) TRGV5#2TRGJ2#1 (156) TRAV8-4#6TRAJ3#1 (1) TRBV7-2#4TRBJ2-7#1 (4) TRBV5-3#1TRBJ2-3#1 (2) TRBV9#2TRBJ2-2P#1 (2) TRBV6-3#1TRBJ2-5#1 (1) TRBV7-2#4TRBJ2-2#1 (1) Unique VJ TCR configurations correspond to sequences recorded at the following IMGT location: http://www.imgt.org/IMGTrepertoire/Probes/Rearrangements%20and%20junctions/human/Hu TRrea.html

TABLE 3 Sanger Sequencing Results PCR & Reads with Total Number Total PCR & Reads with Total Number Total Expected PCR Electrophoresis Detected Primer of Rearranged Reads on Number of Electrophoresis Detected Primer of Rearranged Reads on Number of Product Size Result ‡ Combination Reads Detected Target Input Reads Result ‡ Combination Reads Detected Target Input Reads Primer Combination When Present (bp) ¥ A037 L2D8 TRAV1-1 & TRAJ12 275 Negative 0 877 1155401 1370124 Weak 0 1384 985843 1182258 TRAV1-1 & TRAJ33 282 Weak 0 877 1155401 1370124 Weak 0 1384 985843 1182258 TRAV1-1 & TRAJ49 278 Weak 0 877 1155401 1370124 Weak 0 1384 985843 1182258 TRAV12-2 & TRAJ45 285 Weak 0 877 1155401 1370124 Negative 0 1384 985843 1182258 TRAV17 & TRAJ52 103 Negative 1 877 1155401 1370124 Positive 425 1384 985843 1182258 TRAV27 & TRAJ17 326 Negative 0 877 1155401 1370124 Negative 0 1384 985843 1182258 TRAV27 & TRAJ40 327 Weak 0 877 1155401 1370124 Weak 0 1384 985843 1182258 TRAV29/DV5 & TRAJ26 327 Negative 0 877 1155401 1370124 Negative 0 1384 985843 1182258 TRAV29/DV5 & TRAJ4 315 Weak 0 877 1155401 1370124 Negative 0 1384 985843 1182258 TRAV35 & TRAJ48 333 Negative 0 877 1155401 1370124 Positive 316 1384 985843 1182258 TRAV8-3 & TRAJ42 333 Negative 0 877 1155401 1370124 Negative 0 1384 985843 1182258 TRBV10-3 & TRBJ2-5 296 Negative 0 877 1155401 1370124 Weak 0 1384 985843 1182258 TRBV12-3 & TRBJ1-2 103 Weak 0 877 1155401 1370124 Negative 0 1384 985843 1182258 TRBV18 & TRBJ2-2 264 Negative 0 877 1155401 1370124 Negative 0 1384 985843 1182258 TRBV20-1 & TRBJ2-1 349 Positive 6 877 1155401 1370124 Negative 0 1384 985843 1182258 TRBV5-7 & TRBJ2-2 133 Weak 0 877 1155401 1370124 Negative 0 1384 985843 1182258 TRBV7-8 & TRBJ1-6 257 Negative 0 877 1155401 1370124 Positive 315 1384 985843 1182258 TRBV7-8 & TRBJ2-5 240 Weak 2 877 1155401 1370124 Negative 0 1384 985843 1182258 TRBV9 & TRBJ2-1 336 Positive 2 877 1155401 1370124 Weak 0 1384 985843 1182258 TRGV11 & TRGJ1 297 Negative 8 877 1155401 1370124 Negative 0 1384 985843 1182258 TRGV2 & TRGJP2 325 Positive 13 877 1155401 1370124 Negative 0 1384 985843 1182258 TRGV3 & TRGJ1 241 Weak 3 877 1155401 1370124 Positive 0 1384 985843 1182258 TRGV4 & TRGJ1 254 Positive 17 877 1155401 1370124 Positive 161 1384 985843 1182258 TRGV8 & TRGJ1 263 Positive 8 877 1155401 1370124 Negative 4 1384 985843 1182258 TRGV8 & TRGJP1 266 Positive 2 877 1155401 1370124 Negative 0 1384 985843 1182258 TRGV9 & TRGJ1 182 Positive 9 877 1155401 1370124 Negative 0 1384 985843 1182258 PCR & Reads with Total Number Total PCR & Reads with Total Number Total Expected PCR Electrophoresis Detected Primer of Rearranged Reads on Number of Electrophoresis Detected Primer of Rearranged Reads on Number of Product Size Result ‡ Combination Reads Detected Target Input Reads Result ‡ Combination Reads Detected Target Input Reads Primer Combination When Present (bp) ¥ EZM TIL2 TRAV1-1 & TRAJ12 275 Negative 0 115 1377194 1595646 Negative 0 2095 926207 1145281 TRAV1-1 & TRAJ33 282 Negative 0 115 1377194 1595646 Weak 0 2095 926207 1145281 TRAV1-1 & TRAJ49 278 Negative 0 115 1377194 1595646 Weak 0 2095 926207 1145281 TRAV12-2 & TRAJ45 285 Negative 1 115 1377194 1595646 Weak 0 2095 926207 1145281 TRAV17 & TRAJ52 103 Negative 0 115 1377194 1595646 Negative 0 2095 926207 1145281 TRAV27 & TRAJ17 326 Negative 0 115 1377194 1595646 Weak 0 2095 926207 1145281 TRAV27 & TRAJ40 327 Weak 0 115 1377194 1595646 Weak 0 2095 926207 1145281 TRAV29/DV5 & TRAJ26 327 Negative 0 115 1377194 1595646 Positive 37 2095 926207 1145281 TRAV29/DV5 & TRAJ4 315 Negative 0 115 1377194 1595646 Negative 0 2095 926207 1145281 TRAV35 & TRAJ48 333 Negative 0 115 1377194 1595646 Negative 0 2095 926207 1145281 TRAV8-3 & TRAJ42 333 Negative 0 115 1377194 1595646 Negative 0 2095 926207 1145281 TRBV10-3 & TRBJ2-5 296 Negative 0 115 1377194 1595646 Weak 0 2095 926207 1145281 TRBV12-3 & TRBJ1-2 103 Negative 0 115 1377194 1595646 Negative 0 2095 926207 1145281 TRBV18 & TRBJ2-2 264 Negative 0 115 1377194 1595646 Negative 0 2095 926207 1145281 TRBV20-1 & TRBJ2-1 349 Negative 0 115 1377194 1595646 Weak 8 2095 926207 1145281 TRBV5-7 & TRBJ2-2 133 Weak 0 115 1377194 1595646 Negative 0 2095 926207 1145281 TRBV7-8 & TRBJ1-6 257 Negative 0 115 1377194 1595646 Negative 0 2095 926207 1145281 TRBV7-8 & TRBJ2-5 240 Negative 0 115 1377194 1595646 Weak 0 2095 926207 1145281 TRBV9 & TRBJ2-1 336 Weak 0 115 1377194 1595646 Weak 6 2095 926207 1145281 TRGV11 & TRGJ1 297 Negative 0 115 1377194 1595646 Negative 3 2095 926207 1145281 TRGV2 & TRGJP2 325 Positive 6 115 1377194 1595646 Positive 10 2095 926207 1145281 TRGV3 & TRGJ1 241 Positive 0 115 1377194 1595646 Positive 17 2095 926207 1145281 TRGV4 & TRGJ1 254 Positive 3 115 1377194 1595646 Positive 56 2095 926207 1145281 TRGV8 & TRGJ1 263 Positive 4 115 1377194 1595646 Positive 63 2095 926207 1145281 TRGV8 & TRGJP1 266 Weak 0 115 1377194 1595646 Positive 0 2095 926207 1145281 TRGV9 & TRGJ1 182 Weak 0 115 1377194 1595646 Positive 11 2095 926207 1145281 PCR & Reads with Total Number Total PCR & Reads with Total Number Total Expected PCR Electrophoresis Detected Primer of Rearranged Reads on Number of Electrophoresis Detected Primer of Rearranged Reads on Number of Product Size Result ‡ Combination Reads Detected Target Input Reads Result ‡ Combination Reads Detected Target Input Reads Primer Combination When Present (bp) ¥ OV7 STIM1 TRAV1-1 & TRAJ12 275 Negative 4 2074 1379128 1675034 Negative 0 2796 1066413 1315476 TRAV1-1 & TRAJ33 282 Weak 0 2074 1379128 1675034 Negative 0 2796 1066413 1315476 TRAV1-1 & TRAJ49 278 Weak 0 2074 1379128 1675034 Negative 0 2796 1066413 1315476 TRAV12-2 & TRAJ45 285 Negative 0 2074 1379128 1675034 Weak 238 2796 1066413 1315476 TRAV17 & TRAJ52 103 Weak 0 2074 1379128 1675034 Negative 0 2796 1066413 1315476 TRAV27 & TRAJ17 326 Negative 0 2074 1379128 1675034 Negative 0 2796 1066413 1315476 TRAV27 & TRAJ40 327 Negative 298 2074 1379128 1675034 Weak 0 2796 1066413 1315476 TRAV29/DV5 & TRAJ26 327 Positive 0 2074 1379128 1675034 Negative 2 2796 1066413 1315476 TRAV29/DV5 & TRAJ4 315 Negative 0 2074 1379128 1675034 Negative 0 2796 1066413 1315476 TRAV35 & TRAJ48 333 Negative 0 2074 1379128 1675034 Negative 0 2796 1066413 1315476 TRAV8-3 & TRAJ42 333 Negative 0 2074 1379128 1675034 Weak 185 2796 1066413 1315476 TRAV10-3 & TRBJ2-5 296 Negative 0 2074 1379128 1675034 Negative 0 2796 1066413 1315476 TRBV12-3 & TRBJ1-2 103 Weak 0 2074 1379128 1675034 Negative 0 2796 1066413 1315476 TRBV18 & TRBJ2-2 264 Negative 0 2074 1379128 1675034 Negative 0 2796 1066413 1315476 TRBV20-1 & TRBJ2-1 349 Negative 1 2074 1379128 1675034 Negative 0 2796 1066413 1315476 TRBV5-7 & TRBJ2-2 133 Negative 0 2074 1379128 1675034 Negative 0 2796 1066413 1315476 TRBV7-8 & TRBJ1-6 257 Negative 0 2074 1379128 1675034 Negative 0 2796 1066413 1315476 TRBV7-8 & TRBJ2-5 240 Weak 85 2074 1379128 1675034 Negative 0 2796 1066413 1315476 TRBV9 & TRBJ2-1 336 Positive 0 2074 1379128 1675034 Weak 0 2796 1066413 1315476 TRGV11 & TRGJ1 297 Negative 0 2074 1379128 1675034 Negative 23 2796 1066413 1315476 TRGV2 & TRGJP2 325 Weak 0 2074 1379128 1675034 Positive 11 2796 1066413 1315476 TRGV3 & TRGJ1 241 Negative 7 2074 1379128 1675034 Positive 13 2796 1066413 1315476 TRGV4 & TRGJ1 254 Weak 5 2074 1379128 1675034 Positive 40 2796 1066413 1315476 TRGV8 & TRGJ1 263 Positive 14 2074 1379128 1675034 Positive 24 2796 1066413 1315476 TRGV8 & TRGJP1 266 Positive 197 2074 1379128 1675034 Negative 0 2796 1066413 1315476 TRGV9 & TRGJ1 182 Negative 15 2074 1379128 1675034 Positive 120 2796 1066413 1315476 PCR & Reads with Total Number Total PCR & Reads with Total Number Total Expected PCR Electrophoresis Detected Primer of Rearranged Reads on Number of Electrophoresis Detected Primer of Rearranged Reads on Number of Product Size Result ‡ Combination Reads Detected Target Input Reads Result ‡ Combination Reads Detected Target Input Reads Primer Combination When Present (bp) ¥ SE14-2005 (SUPT1) SE14-2033 (Jurkat) TRAV1-1 & TRAJ12 275 Positive 460 2371 837044 1096080 Negative 0 1554 817921 995632 TRAV1-1 & TRAJ33 282 Negative 0 2371 837044 1096080 Weak 0 1554 817921 995632 TRAV1-1 & TRAJ49 278 Weak 0 2371 837044 1096080 Negative 0 1554 817921 995632 TRAV12-2 & TRAJ45 285 Negative 0 2371 837044 1096080 Negative 0 1554 817921 995632 TRAV17 & TRAJ52 103 Negative 0 2371 837044 1096080 Negative 0 1554 817921 995632 TRAV27 & TRAJ17 326 Negative 0 2371 837044 1096080 Negative 0 1554 817921 995632 TRAV27 & TRAJ40 327 Weak 0 2371 837044 1096080 Weak 0 1554 817921 995632 TRAV29/DV5 & TRAJ26 327 Weak 0 2371 837044 1096080 Weak 0 1554 817921 995632 TRAV29/DV5 & TRAJ4 315 Weak 0 2371 837044 1096080 Negative 1 1554 817921 995632 TRAV35 & TRAJ48 333 Negative 0 2371 837044 1096080 Negative 0 1554 817921 995632 TRAV8-3 & TRAJ42 333 Negative 0 2371 837044 1096080 Negative 0 1554 817921 995632 TRAV10-3 & TRBJ2-5 296 Negative 0 2371 837044 1096080 Weak 0 1554 817921 995632 TRBV12-3 & TRBJ1-2 103 Weak 0 2371 837044 1096080 Positive 138 1554 817921 995632 TRBV18 & TRBJ2-2 264 Negative 0 2371 837044 1096080 Negative 0 1554 817921 995632 TRBV20-1 & TRBJ2-1 349 Negative 0 2371 837044 1096080 Negative 0 1554 817921 995632 TRBV5-7 & TRBJ2-2 133 Weak 0 2371 837044 1096080 Negative 0 1554 817921 995632 TRBV7-8 & TRBJ1-6 257 Negative 0 2371 837044 1096080 Negative 0 1554 817921 995632 TRBV7-8 & TRBJ2-5 240 Negative 0 2371 837044 1096080 Negative 0 1554 817921 995632 TRBV9 & TRBJ2-1 336 Positive 538 2371 837044 1096080 Negative 0 1554 817921 995632 TRGV11 & TRGJ1 297 Negative 0 2371 837044 1096080 Weak 242 1554 817921 995632 TRGV2 & TRGJP2 325 Weak 0 2371 837044 1096080 Negative 0 1554 817921 995632 TRGV3 & TRGJ1 241 Positive 22 2371 837044 1096080 Negative 0 1554 817921 995632 TRGV4 & TRGJ1 254 Positive 25 2371 837044 1096080 Negative 0 1554 817921 995632 TRGV8 & TRGJ1 263 Negative 0 2371 837044 1096080 Weak 146 1554 817921 995632 TRGV8 & TRGJP1 266 Negative 0 2371 837044 1096080 Negative 0 1554 817921 995632 TRGV9 & TRGJ1 182 Weak 0 2371 837044 1096080 Negative 0 1554 817921 995632 PCR & Reads with Total Number Total PCR & Reads with Total Number Total Expected PCR Electrophoresis Detected Primer of Rearranged Reads on Number of Electrophoresis Detected Primer of Rearranged Reads on Number of Product Size Result ‡ Combination Reads Detected Target Input Reads Result ‡ Combination Reads Detected Target Input Reads Primer Combination When Present (bp) ¥ SE14-2034 (MOLT4) SE14-2035 (CEM) TRAV1-1 & TRAJ12 275 Negative 0 1723 741549 906513 Negative 0 1744 981779 1289677 TRAV1-1 & TRAJ33 282 Positive 347 1723 741549 906513 Weak 0 1744 981779 1289677 TRAV1-1 & TRAJ49 278 Negative 0 1723 741549 906513 Negative 0 1744 981779 1289677 TRAV12-2 & TRAJ45 285 Negative 0 1723 741549 906513 Negative 0 1744 981779 1289677 TRAV17 & TRAJ52 103 Negative 0 1723 741549 906513 Positive 0 1744 981779 1289677 TRAV27 & TRAJ17 326 Negative 0 1723 741549 906513 Negative 0 1744 981779 1289677 TRAV27 & TRAJ40 327 Negative 0 1723 741549 906513 Positive 506 1744 981779 1289677 TRAV29/DV5 & TRAJ26 327 Negative 0 1723 741549 906513 Negative 0 1744 981779 1289677 TRAV29/DV5 & TRAJ4 315 Negative 0 1723 741549 906513 Positve 751 1744 981779 1289677 TRAV35 & TRAJ48 333 Negative 0 1723 741549 906513 Negative 0 1744 981779 1289677 TRAV8-3 & TRAJ42 333 Negative 0 1723 741549 906513 Weak 0 1744 981779 1289677 TRAV10-3 & TRBJ2-5 296 Positive 379 1723 741549 906513 Negative 0 1744 981779 1289677 TRBV12-3 & TRBJ1-2 103 Negative 0 1723 741549 906513 Negative 0 1744 981779 1289677 TRBV18 & TRBJ2-2 264 Negative 0 1723 741549 906513 Negative 0 1744 981779 1289677 TRBV20-1 & TRBJ2-1 349 Positive 551 1723 741549 906513 Negative 0 1744 981779 1289677 TRBV5-7 & TRBJ2-2 133 Negative 0 1723 741549 906513 Weak 0 1744 981779 1289677 TRBV7-8 & TRBJ1-6 257 Negative 0 1723 741549 906513 Negative 0 1744 981779 1289677 TRBV7-8 & TRBJ2-5 240 Negative 0 1723 741549 906513 Negative 0 1744 981779 1289677 TRBV9 & TRBJ2-1 336 Negative 0 1723 741549 906513 Positive 1 1744 981779 1289677 TRGV11 & TRGJ1 297 Negative 0 1723 741549 906513 Weak 0 1744 981779 1289677 TRGV2 & TRGJP2 325 Positive 275 1723 741549 906513 Weak 0 1744 981779 1289677 TRGV3 & TRGJ1 241 Negative 0 1723 741549 906513 Positive 222 1744 981779 1289677 TRGV4 & TRGJ1 254 Negative 0 1723 741549 906513 Positive 0 1744 981779 1289677 TRGV8 & TRGJ1 263 Negative 0 1723 741549 906513 Negative 0 1744 981779 1289677 TRGV8 & TRGJP1 266 Negative 0 1723 741549 906513 Negative 0 1744 981779 1289677 TRGV9 & TRGJ1 182 Negative 0 1723 741549 906513 Weak 0 1744 981779 1289677 

1. A method of capturing a population of T-Cell receptor and/or immunoglobulin sequences with variable regions within a patient sample, said method comprising: extracting/preparing DNA fragments from the patient sample; ligating a nucleic acid adapter to the DNA fragments, the nucleic acid adapter suitable for recognition by a pre-selected nucleic acid probe; capturing DNA fragments existing in the patient sample using a collection of nucleic acid hybrid capture probes, wherein each capture probe is designed to hybridize to a known V gene segment and/or a J gene segment within the T cell receptor and/or immunoglobulin genomic loci.
 2. The method of claim 1, further comprising sequencing the captured DNA fragments, wherein the sequencing can be used to determine clonotypes within the patient sample.
 3. The method of claim 1, wherein said sequencing is optimized for short read sequencing.
 4. The method of claim 2, further comprising amplifying the population of sequences using nucleic acid amplification probes/oligonucleotides that recognize the adapter prior to said sequencing.
 5. The method of claim 1, further comprising fragmenting DNA extracted from the patient sample to generate the DNA fragments.
 6. The method of claim 1, wherein the ligating step is performed before the capturing step.
 7. The method of claim 1, wherein the capturing step is performed before the ligating step.
 8. The method of claim 1, wherein the patient sample comprises tissue, urine, cerebral spinal fluid, saliva, feces, ascities, pleural effusion, blood or blood plasma.
 9. The method of claim 1, wherein the patient sample comprises cell-free nucleic acids in blood plasma.
 10. The method of claim 1, wherein the hybrid capture probes are at least 30 bp in length.
 11. The method of claim 10, wherein the hybrid capture probes are between 60 bp and 150 bp in length, preferably between 80 bp and 120 bp in length, and further preferably about 100 bp in length.
 12. The method of claim 1, wherein the hybrid capture probes hybridize to at least 30 bp, preferably 50 bp, more preferably 100 bp of the V gene segment and/or J gene segment.
 13. The method of claim 1, wherein the hybrid capture probes hybridize to at least a portion of the V gene segment and/or J gene segment at either the 3′ end or the 5′ end of the V gene segment and/or J gene segment respectively.
 14. The method of claim 1, wherein the screening probes hybridize to at least a portion of the V gene segment.
 15. The method of claim 1, wherein the screening probes hybridize to at least a portion of the V gene segment at the 3′ end.
 16. The method of claim 1, wherein hybridizing comprises hybridizing under stringent conditions, preferably very stringent conditions.
 17. The method of claim 1, wherein the collection of nucleic acid hybrid capture probes comprise at least 2, 5, 10, 20, 30, 80, 100, 300, 400, 500, 600, 700, 800 or 900 unique hybrid capture probes.
 18. The method of claim 1, wherein the collection of nucleic acid hybrid capture probes is sufficient to capture at least 50%, 60%, 70%, 80%, 90% or 99% of known T-Cell receptor and/or immunoglobulin loci clonotypes.
 19. The method of claim 1, wherein the hybrid capture probes are immobilized on an array.
 20. The method of claim 1, wherein the hybrid capture probes comprise a label.
 21. The method of claim 20, wherein the label is used to distinguish between sequences bound to the screening probes and unbound double stranded fragments.
 22. The method of claim 1, wherein the adapter is designed to permit sequencing of the DNA fragment and/or barcoding of the DNA fragment.
 23. The method of claim 1, wherein preparing the DNA fragments comprises extracting RNA from the patient sample and preparing corresponding cDNA.
 24. The method of claim 1, further comprising a depletion step, comprising depleting the DNA fragments of non-rearranged sequences using probes that recognize nucleic acid sequences adjacent to V and/or J gene segments in the genome.
 25. The method of claim 24, wherein the capturing of DNA fragments using V gene segment and J gene segment hybrid capture probes is performed in separate steps, and in any order with the depletion step, preferably in the following order: J gene capture, depletion, then V gene capture. 26.-32. (canceled)
 33. A method for characterizing the immune repertoire of a subject, the immune repertoire comprising the subject's T-Cell population, the method comprising the method of claim 1, followed by a method comprising: (j) identifying all sequences containing a V gene segment from the sequences of the DNA fragments by aligning the sequences of the DNA fragments to a library of known V gene segment sequences; (k) trimming the identified sequences in (i) to remove any sequences corresponding to V gene segments to produce a collection of V-trimmed nucleotide sequences; (l) identifying all sequences containing a J gene segment in the population of V-trimmed nucleotide sequences by aligning the V-trimmed nucleotide sequences to a library of known J gene segment sequences; (m) trimming the V-trimmed nucleotide sequences identified in (1) to remove any sequences corresponding to J gene segments to produce VJ-trimmed nucleotide sequences; (n) identifying any D gene segment comprised in the VJ-trimmed nucleotide sequences identified in (m) by aligning the VJ-trimmed nucleotide sequences to a library of known D gene segment sequences; (o) for each VJ-trimmed nucleotides sequence identified in (m), assembling a nucleotide sequence comprising the V gene segment any D gene segment, and the J gene segment identified in steps (i), (n) and (l) respectively; (p) selecting from the nucleotide sequence assembled in step (o) a junction nucleotide sequence comprising at least the junction between the V gene segment and the J gene segment, including any D gene segment, the junction nucleotide sequence comprising between 18 bp and 140 bp; and optionally (q) and (r); (q) translating each reading frame of the junction nucleotide sequence and its complementary strand to produce 6 translated sequences; and (r) comparing the 6 translated sequences to a library of known CDR3 regions of T-Cell receptor and/or immunoglobulin sequences to identify the CDR3 region in the DNA fragments. 34.-53. (canceled) 